Carbapenem derivatives

ABSTRACT

The carbapenem derivatives represented by the following formula (I) is disclosed. These compounds have strong anti-bacterial activities against bacteria including methicillin resistant  Staphylococcus aureus , penicillin resistant  Streptococcus pneumoniae , Enterococci, influenza, and β-lactamase producing bacteria, and have high stabilities to DHP-1                    
     wherein R 1  represents hydrogen or methyl, either one of R 2 , R 3 , R 4 , or R 5  represents the bond to the 2-position on the carbapenem ring, and the remaining three respectively represent hydrogen, halogen, nitro, cyano, alkyl, cycloalkyl, alkylthio, alkenyl, formyl, alkylcarbonyl, alkoxycarbonyl, aminosulfonyl, aryl carbonyl, aryl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, lower alkoxyiminomethyl, or hydroxyiminomethyl, R 6  is not present or represents alkyl, cycloalkyl, or alkenyl, and R is not present, or represents hydrogen or a group which may be metabolically hydrolyzed in the body, provided that when R 6  is not present, R represents hydrogen or a group which may be metabolically hydrolyzed in the body, and when R 6  is present, R is not present, and the compound forms an inner salt.

This application is a 371 application of International Application No.PCT/JP98/00347, filed Jan. 28, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a carbapenem compound which hasexcellent antimicrobial activity and wide range of anti-microbialspectrum, and can be administered not only as an injection but alsoorally. More particularly, the present invention relates to a novelcarbapenem derivative which has a substituted or unsubstitutedimidazo[5,1-b]thiazole group or a substituted or unsubstitutedimidazo[5,1-b]thiazolium group at the 2-position on the carbapenem ring,or a salt thereof.

2. Background Art

Carbapenem derivatives, by virtue of potent antibacterial activityagainst a wide spectrum of bacteria, have been energetically studied asa highly useful β-lactam agent, and Imipenem, Panipenem, and Meropenemhave been clinically used.

Both Imipenem and Panipenem, however, are used as a mixture due toinstability against renal dehydropeptidase-1 (“DHP-1”) in the case ofImpenem and in order to reduce nephrotoxicity in the case of Panipenem.Meropenem which has recently been marketed has a methyl group at the1β-position, so that it has increased stability to DHP-1 and thus can beused alone.

However, a need still exists for a drug having higher stability toDHP-1. Furthermore, drugs effective for methicillin resistantStaphylococcus aureus (“MRSA”), penicillin resistant Streptococcuspneumoneae (“PRSP”), resistant Pseudomonas aeruginosa and enterococciwhich have recently become serious problems as well as influenza havebeen demanded as well.

Some of the present inventors have previously reported the carbapenemderivatives having a novel heteroaromatic ringimidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position on thecarbapeneni ring in WO 96/028455 and the carbapenem derivatives havingan imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the2-position of the carbapenem ring in PCT/JP 97/04270.

Further, WO 96/034868 and Japanese Patent Laid-Open Publication No.273876/1992 disclose the carbapenem derivatives in which a carbon atomon the heteroaromatic ring is bonded to the 2-position of the carbapenemring. However, there have been described no specific data on theanti-microbial activities or effectiveness for these derivatives. Therehave been described neither bicyclic heteroaromatic rings nor carbapenemrings having imidazo[5,1-b]thiazole group.

SUMMARY OF THE INVENTION

The present inventors have now found that novel carbapenem derivativeshaving a substituted or unsubstituted imidazo[5,1-b]thiazole group or asubstituted or unsubstituted imidazo[5,1-b]thiazolium group at the2-position on the carbapenem ring have high anti-microbial activitiesagainst MRSA, PRSP, enterococci, influenza and β-lactamase producingbacteria, and high stabilities to DHP-1. The present invention is basedon such findings.

Thus, the object of the present invention is to provide novel compoundswhich have wide range of anti-microbial activities, especially highanti-microbial activities against microorganisms including MRSA, PRSP,enterococci, influenza and β-lactamase producing bacteria, and highstabilities to DHP-1.

Thus, the present invention provides a compound represented by theformula (I), or a pharmacologically acceptable salt thereof:

wherein,

R¹ represents hydrogen or methyl,

R², R³, R⁴, and R⁵, either one of which represents the bond to the2-position on the carbapenem ring, and the remaining three groups, whichmay be the same or different, respectively represent

hydrogen,

halogen,

nitro,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected by the group consisting of halogen,nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy,amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino,carbamoyl, N-lower alkylcarbarnoyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-loweralkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,

lower cycloalkyl, in which one or more hydrogen atoms on the cycloalkylmay be substituted by a group selected from the group consisting oflower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy,hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alko)rycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylainino,aiminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,lower alkylthio,

C₂₋₄ alkenyl, in which one or more hydrogen atoms on the alkenyl may besubstituted by a group selected from the group consisting of loweralkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, loweralkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

lower alkylsulfonyl,

arylsulfonyl,

aminosulfonyl,

arylcarbonyl,

aryl, in which one or more hydrogen on the aryl may be substituted by agroup selected from the group consisting of lower alkyl, halogen, nitro,cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino,N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl,lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, and

(N,N-di-lower alkylamino)sulfonylamino, carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or hydroxyiminomethyl,

R⁶ is not present, or represents lower alkyl, in which one or morehydrogen atoms on the alkyl may be substituted by a group selected fromthe group consisting of halogen, nitro, cyano, lower cycloalkyl, loweralkylthio, lower alkoxy, hydroxy, amino, N-lower alkylainino, formyl,lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl,formylamino, lower alkylcarbonylamino, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-loweralkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-loweralkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl,

lower cycloalkyl, in which one or more hydrogen atoms on the cycloalkylmay be substituted by a group selected from the group consisting oflower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy,hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, or

C2-4 alkenyl, in which one or more hydrogen atoms on the alkenyl may besubstituted by a group selected from the group consisting of loweralkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, loweralkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,and

R is not present, or represents hydrogen or a group which may bemetabolically hydrolyzed in the body,

provided that when R6 is not present, R represents hydrogen or a groupwhich may be metabolically hydrolyzed in the body, and when R6 ispresent, R is not present, and the compound forms an inner salt.

DETAILED DESCRIPTION OF THE INVENTION

Definition

As used herein, the term “lower alkyl” or “lower alkoxy” as a group or apart of a group means a straight chain or branched chain alkyl oralkyloxy having 1-6 carbon atoms, preferably 1-4 carbon atoms. Theexamples of the lower alkyl include methyl, ethyl, N-propyl, isopropyl,N-butyl, i-butyl, s-butyl, t-butyl, N-pentyl, N-hexyl, and the like.Further, the lower alkoxy includes by way of example methoxy, ethoxy,N-propoxy, i-propoxy, N-butoxy, i-butoxy, s-butoxy, t-butoxy, and thelike.

The term “lower cycloalkyl” means monocyclic alkyl having 3-6 carbonatoms.

The term “halogen” herein means fluorine, chlorine, bromine, or iodine.

Further, the term “aryl” means preferably phenyl or naphthyl.

Compound

In the formul(I), any one of R2, R3, R4, and R5 represents the bond tothe 2-position on the carbapenem ring.

The remaining three groups, which may be the same or different,respectively represent hydrogen, halogen, nitro, cyano, lower alkylwhich may be substituted, lower cycloalkyl which may be substituted,lower alkylthio, C2-4 alkenyl which may be substituted, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfoiny, arylsulfonyl,aminosulionyl, arylcarbonyl, aryl which may be substituted, carbamoyl,N-lower alkylcarbamoyl, N,N-dilower alkylaminocarbonyl, loweralkoxyiminoiiiethyl, or hydroxyiminomethyl. According to the preferredembodiment of the present invention, the remaining three groups ispreferably hydrogen, halogen, cyano, lower alkyl which may besubstituted, formyl, lower alkylcarbonyl, lower alkoxycarbonyl,aminosulfonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaininocarbonyl, lower alkoxyiminomethyl, or hydroxyiminomethyl,more preferably hydrogen, chlorine, cyano, lower alkyl which may besubstituted, formyl, lower alkylcarbonyl, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, or N,N-di-lower alkylaminocarbonyl.

In R², R³, R⁴, and R5 which represent lower alkyl, one or more hydrogenatoms on the lower alkyl may be substituted by halogen, nitro, cyano,lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-loweralkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl. According to the preferredembodiment of the present invention, the substituent includes preferablylower alkoxy, hydroxy, formylamino, and carbamoyl, particularly loweralkoxy, hydroxy, and formylamino. The substituted alkyl includes forexample aminomethyl, hydroxymethyl, 2-hydroxyethyl, carbamoylmethyl,2-carbamoylethyl, 2-fluoroethyl, cyclopropylmethyl,2-(N-methylcarbamoyl)ethyl, N,N-dimethylcarbamoylmethyl,2-(N,N-dimethylcarbamoyl)ethyl, 2-aminosulfonylethyl,aminosulfonylaminomethyl, 2-(aminosulfonylamino)ethyl, methoxymethyl,ethoxycarbonylmethyl, formylaminomethyl, methoxyiminomethyl,hydroxyiminomethyl, benzyl.

In R², R³, R⁴, and R⁵ which represent cycloalkyl, one or more hydrogenatoms on the cycloalkyl may be substituted by a group selected from thegroup consisting of lower alkyl, halogen, nitro, cyano, lower alkylthio,lower alkoxy, hydroxcy, amino, N-lower alkylamino, formyl, loweralkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl,formylamino, lower alkylcarbonylamino, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-loweralkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-loweralkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl. According to the preferredembodiment of the present invention, the substituent includes forexample lower alkoxy, hydroxy, formylamino, and carbamoyl, particularlylower alkoxy, hydroxy, and formylamino.

Furthermore, in R², R³, R⁴, and R⁵ which represent alkenyl, one or morehydrogen atoms on the alkenyl may be substituted, and the substituentincludes for example a group selected from the group consisting of loweralkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, loweralkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamnoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl.According to the preferred embodiment of the present invention, thepreferred substituent includes for example lower alkoxy, hydroxy,formylamino, and carbamoyl, particularly lower alkoxy, hydroxy, andformylamino.

The arylcarbonyl represented by R², R³, R⁴, and R⁵ includes preferablyphenylcarbonyl or naphthylcarbonyl.

The aryl represented by R², R³, R⁴, and R⁵ includes preferably phenyl ornaphthyl. Furthermore, one or more hydrogen atoms on the aryl may besubstituted by lower alkyl, halogen, nitro, cyano, lower cycloalkyl,lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino,formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, and (N,N-di-loweralkylamino)sulfonylamino. According to the preferred embodiment of thepresent invention, the preferred substituent includes preferably loweralkoxy, hydroxy, formylamino, and carbamoyl, particularly lower alkoxy,hydroxy, and formylamino.

In the formul(I), R⁶ is not present, or represents lower alkyl, lowercycloalkyl, or C₂₋₄ alkenyl, preferably lower alkyl. Further, R is notpresent, or represents hydrogen or a group which may be metabolicallyhydrolyzed in the body. In the formul(I), when R⁶ is not present, Rrepresens hydrogen or a group which may be metabolically hydrolyzed inthe body, and when R⁶ is present, R is not present, and the compoundforms an inner salt. The inner salt formed by the presence of R⁶ and theabsence of R means the compound represented by the following formul(II):

One or more hydrogen atoms on the lower alkyl represented by R⁶ may besubstituted by a group selected from the group consisting of halogen,nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy,amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino,carbamoyl, N-lower alkylcarbamnoyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino )sulfonylamino, aminosulfonylamino,(N,N-di-lower alkylamino)sulfonylamino, and aryl.

Further, one or more hydrogen atoms on the lower cycloalkyl representedby R⁶ may be substituted by a group selected from the group consistingof lower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy,hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl.

One or more hydrogen atoms on the C₂₋₄ alkenyl represented by R6 may besubstituted, and include a group selected from the group consisting oflower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio,lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, loweralkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl,formylamino, lower alkylcarbonylamino, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-loweralkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-loweralkylainino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl.

The group represented R which may be metabolically hydrolyzed in thebody is preferably ester and includes for example loweralkylcarbonyloxy-lower-alkyl, lower cycloalkylcarbonyloxy-lower-alkyl,lower cycloalkylmethylcarbonyloxy-lower-alkyl, loweralkenylcarbonyloxy-lower-alkyl, arylcarbonyloxy-lower-alkyl,tetrahydrofuranylcarbonyloxymethyl, lower alkoxy-lower-alkyl, loweralkoxy-lower-alkoxy-lower-alkyl, arylmethyloxy-lower-alkyl,arylmethyloxy-lower-alkoxy-lower-alkyl, loweralkyloxycarbonyloxy-lower-alkyl, lowercycloalkyloxycarbonyloxy-lower-alkyl, lowercycloalkylmethoxycarbonyloxy-lower-alkyl,aryloxycarbonyloxy-lower-alkyl, 3-phthalidyl in which the aromatic ringmay be substituted, 2-(3-phthalidylidene)ethyl in which the aromaticring may be substituted, 2-oxotetrahydrofuran-5-yl, 2-oxo-5-loweralkyl-1,3-dioxolen-4-ylmethyl. Preferred example includes loweralkylcarbonyloxy-lower-alkyl, lower cycloalkylcarbonyloxy-lower-alkyl,lower alkyloxycarbonyloxy-lower-alkyl, lowercycloalkyloxycarbonyloxy-lower-alkyl, lowercycloalkylmethoxycarbonyloxy-lower-alkyl,aryloxycarbonyloxy-lower-alkyl, 3-phthalidyl in which the aromatic ringmay be substituted, 2-(3-phthalidylidene)ethyl in which the aromaticring may be substituted, 2-oxotetrahydrofuran-5-yl, and 2-oxo-5-loweralkyl-1,3-dioxolen-4-ylmethyl, more preferably, pivaloyloxymethyl ester,acetoxymethyl ester, 1-(acetoxy)ethyl ester,(1-methylcyclohexan-1-yl)carbonyloxymethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester,1-(cyclohexyloxycarbonyloxy)ethyl ester, cyclohexyloxycarbonyloxymethylester, 3-phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester,1-[(cyclohexylmethoxy)carbonyloxy]ethyl ester,1-[(2-methylcyclohexan-1-yl)oxycarbonyloxy]ethyl ester,cyclopentyloxycarbonyloxymethyl ester, (Z)-2-(3-phthalidylidene)ethylester, (1R,2S,5R)-(l)-menthyloxycarbonyloxymethyl ester,(1S,2R,5S)-(d)-menthyloxycarbonyloxym ethyl ester,1-(phenyloxycarbonyloxy)etthyl ester, phenyloxycarbonyloxymethyl ester,and 1-(cyclohexyloxycarbonyloxy)-N-propyl ester.

Further, one or more hydrogen atoms on the lower alkyl, lowercycloalkyl, C₂₋₄ alkenyl and aryl as a part of the above ester m oietiesmay be substituted by, for example, lower alkyl, halogen, nitro, cyano,lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-loweralkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylainino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl, preferably lower alkyl, loweralkoxy, hydroxy, formylamino, or carbamoyl.

Furthermore, when the above ester moiety is 3-phthalidyl in which thearomatic ring may be substituted or 2-(3-phthalidylidene)ethyl in whichthe aromatic ring may be substituted, the substituent includes loweralkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, loweralkoxy, hydroxy, amino, N-lower alrylamino, formyl, lower alkylcarbonyl,arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonyl amino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, aryl,preferably lower alkoxy, hydroxy, formylamino, and carbamoyl.

The preferred compounds of the formul(I) according to the presentinvention include those in which R⁶ is not present, R representshydrogen or a group which may be metabolically hydrolyzed in the body.

The compounds in which R⁶ is not present preferably inclouse those inwhich

R¹ represents hydrogen or methyl,

R², R³, R⁴, and R⁵, except the one representing the bond to the2-position on the carbapenem ring, which may be the same or different,respectively represent,

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of halogen,nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy,amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-loweralkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,more preferably the alkyl is unsubstituted, or the one substituted withlower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl. Among the above compounds, more preferred compoundsinclude those in which R represents lower alkylcarbonyloxy-lower-alkyl,lower cycloalkylcarbonyloxy-lower-alkyl, loweralkyloxycarbonyloxy-lower-alkyl, lowercycloalkyloxycarbonyloxy-lower-alkyl, lowercycloalkylmethoxycarbonyloxy-lower-alkyl,aryloxycarbonyloxy-lower-alkyl, 2-oxo-5-loweralkyl-1,3-dioxolen-4-ylmethyl, 3-phthalidyl in which the aromatic ringmay be substituted, or 2-(3-phthalidylidene)ethyl in which the aromaticring may be substituted is preferred.

Another preferred compounds in which R⁶ is not present includes those inwhich

R¹ represents methyl,

R² represents the bond to the 2-position on the carbapenem ring,

R³, R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl;

those in which

R¹ represents hydrogen,

R² represents the bond to the 2-position on the carbapenem ring,

R³, R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl;

those in which,

R¹ represents methyl,

R³ represents the bond to the 2-position on the carbapenem ring,

R², R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl;

those in which

R¹ represents hydrogen,

R³ represents the bond to the 2-position on the carbapeneim ring

R², R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl;

those in which

R¹ represents hydrogen or methyl,

R⁴ represents the bond to the 2-position on the carbapenem ring,

R², R³, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl; and

those in which

R¹ represents hydrogen or methyl,

R⁵ represents the bond to the 2-position on the carbapenem ring,

R², R³, and R⁴, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl.

Another preferred compounds of the formul(I) according to the presentinvention include those in which R⁶ is present, R is not present, andthe compound forms an inner salt.

The compounds in which R⁶ is present, and the compound forms an innersalt include more preferably those in which

R¹ represents hydrogen or methyl,

R², R³, R⁴, R⁵, and R⁶, except the one representing the bond to the2-position on the carbapenem ring, which may be the same or different,respectively represent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by halogen, nitro, cyano, lower cycloalkyl, lower alkylthio,lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, loweralkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl,formylamino, lower alkylcarbonylamino, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-loweralkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-loweralkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl.

Among these compounds, more preferred compounds includes those in which

R², R³, R⁴, and R⁵, except the one representing the bond to the2-position on the carbapenem ring, represent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which, may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl.

Another preferred compounds in which R⁶ is present, and the compoundforms an inner salt includes those in which

R¹ represents methyl,

R² represents the bond to the 2-position on the carbapenem ring

R³, R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl;

those in which

R¹ represents hydrogen,

R² represents the bond to the 2-position on the carbapenem ring,

R³, R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl;

those in which

R¹ represents methyl,

R³ represents the bond to the 2-position on the carbapenem ring,

R², R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl;

those in which

R¹ represents hydrogen,

R³ represents the bond to the 2-position on the carbapenem ring,

R², R⁴, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl;

those in which

R¹ represents hydrogen or methyl,

R⁴ represents the bond to the 2-position on the carbapenem ring,

R², R³, and R⁵, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl; and

those in which

R¹ represents hydrogen or methyl,

R⁵ represents the bond to the 2-position on the carbapenem ring,

R², R³, and R⁴, which may be the same or different, respectivelyrepresent

hydrogen,

halogen,

cyano,

lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, and formylamino,

formyl,

lower alkylcarbonyl,

lower alkoxycarbonyl,

aminosulfonyl,

carbamoyl,

N-lower alkylcarbamoyl,

N,N-di-lower alkylaminocarbonyl,

lower alkoxyiminomethyl, or

hydroxyiminomethyl, and

R⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl.

The further preferred compounds of the present invention include thosein which R² or R³ represents the bond to the 2-position on thecarbapenem ring.

Furthermore, the another preferred compounds of the present inventioninclude those in which R⁶ represents alkyl having 1-2 carbon atoms whichmay be substituted by carbamoyl, fluorine, or hydroxy.

The another preferred compounds of the present invention include thosein which

R² represents the bond to the 2-position on the carbapenem ring,

all of R³, R⁴, and R⁵ represent hydrogen, or

both of R³ and R⁴ represent hydrogen, and R⁵ represents a group selectedfrom the group consisting of lower alkyl which may be substituted byformylamino or lower alkoxy, chlorine, formyl, lower alkylcarbonyl,cyano, carbamoyl, N-lower alkylcarbamoyl, and N,N-di-loweralkylaminocarbonyl.

The another preferred compounds of the present invention include thosein which R² represents the bond to the 2-position on the carbapenemring, and R³ represents methyl.

Furthermore, the another preferred compounds of the present inventionincludes those in which R³ represents the bond to the 2-position on thecarbapenem ring, both of R² and R⁴ represent a hydrogen atom, and R⁵represents hydrogen or cyano.

The compound represented by the formula (I) according to the presentinvention can exist as a salt, and the preferred salt is apharmacologically acceptable salt. Such a salt includes for exampleinorganic salts such as lithium, sodium, potassium, calcium, ormagnesium salts, an ammonium salt, salts with organic bases such astriethylamine or diisopropylethylamine, salts with mineral acids such ashydrochloric acid, sulfuric acid, phosphoric acid, or nitric acid, orsalts with organic acids such as acetic acid, carbonic acid, citricacid, malic acid, oxalic acid, or methanesulfonic acid, preferably aninner salt, or sodium or potassium salt.

The specific examples of the compounds of the formula (I) according tothe present invention include:

1.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

2. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

3.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt);

4.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

5. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

6.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate(inner salt);

7.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid;

8.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid;

9. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

10.(1S,5R,6S)2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

11.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid;

12. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

13.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

14.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

15.(1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

16.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid

17.(1S,5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-mnethyl-1-carbapen-2-em-3-carboxylate(inner salt);

18. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methyirimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

19.(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

20.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid;

21.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid;

22.(1S,5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

23. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

24.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid;

25. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

26. Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

27. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

28.(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

29.(5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt);

30. (1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

31. Pivaloyloxymethyl (1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

32.(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]-thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

33.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

34. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

35.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

36.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid;

37. Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

38. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

39. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

40.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

41.(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]-thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt);

42.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid;

43. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

44.(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

45.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid;

46. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate;

47. Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

48.(1S,5R,6S)-2-(7-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

49. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

50.(5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid (inner salt);

51 Acetoxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

52. 1-(acetoxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatecarboxylate (diastereomer mixture);

53. (1-methylcyclohexan-1-yl)carbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

54. 1-(ethoxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

55. 1-(isopropoxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

56. 1-(cyclohexyloxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

57. Cyclohexyloxycarbonyloxy methyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

58. Phthalidyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

59. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

60. 1-[(cyclohexymethoxy)carbonyloxy]ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

61. 1-[(2-methylcyclohexan-1-yl)oxycarbonyloxy]ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

62. Cyclopentyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

63. (Z)-2-(3-phthlidylidene)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

64. (1R,2S,5R)-(1)-menthyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

65.(1S,2R,5S)-(d)-menthyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

66. 1-(phenyloxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

67. phenyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

68. 1-(cyclohexyloxycarbonyloxy)-N-propyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

69.(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid

70. Pivaloyoxymethyl(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

71. Potassium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate;

72. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate;

73.(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

74. Pivaloyloxymethyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

75.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

76.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

77. Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

78.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

79. Sodium(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

80.(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

81. Pivaloyloxymethyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

82.(1S,5R,6S)-2-(5-formyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

83. Pivaloyloxyinethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-carbapen-2-em-3-carboxylate;

84. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate;

85.(5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt);

86. Pivaloyloxymethyl(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

87.(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt);

88. Sodium(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

89. Sodium(1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

90. Acetoxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

91. 1-(acetoxy)ethyl(5R,6S)-2-(imidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

92. (1-methylcyclohexan-1-yl)carbonyloxymethyl(5R,6S)-6-(1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]-thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

93. 1-(ethoxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

94. 1-(isopropoxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]-thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

95. 1-(cyclohexyloxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

96. cyclohexyloxycarbonyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

97. 3-phthalidyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture);

98. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl(5R,6S)-6-(((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

99. Pivaloyloxymethyl(1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

100. Sodium (5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

101. Pivaloyloxymethyl (5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

102.(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

103. Pivaloyloxymethyl(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

104.(1S,5R,6S)-6-((1R)-1-hydroxyethy)-1-methyl-2-(5,6,7-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt);

105. Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

106. Sodium(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

107. Pivaloyloxpymethyl(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

108.(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

109. Pivaloyloxymethyl(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

110. Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-carbapen-2-em-3-carboxylate;

111. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-carbapen-2-em-3-carboxylate;

112. Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

113. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]-thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

114. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate;

115.(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]-thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

116. Pivaloyloxymethyl(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

117.(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid;

118. Pivaloyloxymethyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]-thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

119.(5R,6S)-2-(5-carbamoy3imidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

120.(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

121. Pivaloyloxymethyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

122.(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

123. Pivaloyloxymethyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

124.(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

125. Pivaloyloxymethyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

126.(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt);

127.(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

128. Pivaloyloxymethyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

129.(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

130. Pivaloyloxymethyl(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

131.(5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazoliuin-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt);

132.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-trimethylimidazo[5,1-b]thiazoliunm-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt);

133. Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

134. Pivaloyloxymethyl(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

135.(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

136.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid (geometrical isomer derived from a high polar oxime isomer as a rawmaterial);

137.(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylicacid;

138. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;

139. Sodium(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

140. Pivaloyloxymethyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

141. Sodium (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carhoxylate;

142. Pivaloyloxymethyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate;

143.(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid;

144. Pivaloyloxymethyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]-thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

145.(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylicacid;

146. Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate;

147. Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a high polar oxime isomer as a rawmaterial);

148. Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methooxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometricalisomer derived from a high polar oxime isomer as a raw material).

Preparation of the Compounds

The compounds according to the present invention can be prepared by avariety of methods. The preferred preparation methods are shown below.

Process (1)

Fisrt, the compound of the formula (I) according to the presentinvention can be prepared according to the following reaction scheme.

wherein

R¹, R², R³, R⁴ and R⁵ have the same meaning as defined in the formula(I),

R⁷ represents hydrogen or a hydroxyl protecting group such ast-butyldimethylsilyl, trimethylsilyl, triethylsilyl,4-nitrobenzyloicycarbonyl, 4-methoxybenzyloxycarbonyl,

R⁸ represents a carboxyl protecting group such as 4-nitrobenzyl,4-methoxybenzyl, diphenylmethyl, t-butyldimethylsilyl,

R⁹ represents lower alkyl, preferably n-butyl and methyl.

The compound of the formula (III) can be prepared by the ordinarymethod, and the tin compound of the formula (V) can be prepared by amethod described below.

In the first step, the compound of the formula (III) can be convertedinto the compound of the formula (IV) by the following method. Thecompound (IV) can be prepared by reacting the compound of the theformula (III) with one (1) equivalent or an excessive amount ofanhydrous trifluoromethanesulfonic acid in the presence of an organicbase, preferably diisopropylethylamine in an amount of one (1)equivalent or an excessive amount to anhydrous trifluoromethanesulfonicacid in an inert solvent such as acetonitrile, tetrahydrofuran,dichloromethane, and toluene, and the mixed solvent thereof at atemperature of −50° C.-+50° C. for 10 minutes-24 hours, and thensubjecting the reaction mixture to the usual purification procedure.

In the second step, the compound of the formula (IV) can be convertedinto the compound of the formula (VI) by the following method. Thecompound of the formula (VI) can be prepared by reacting the compound ofthe formula (IV) with one (1) equivalent or an excessive amount of thecompound of the formula (V) in the presence of 0.001-1 equivalent of apalladium catalyst such as tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)-dipalladium(0), ortris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, 0.01-1equivalent of a phosphine ligand such as triphenylphosphine,tri-2-furylphosphine, or tri-2-thienylphosphine,tris(2,4,6-trimethoxyphenyl)phosphine, and 1-10 equivalents of anadditive such as zinc chloride, lithium chloride, or cesium fluoridealone or in combination thereof in an inert solvent such astetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, acetone,ethanol, dimethylsulfoxide, sulfolane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, or hexamethylphosphorictriamide, or a mixed solvent thereof at 0-100° C. for 10 minutes-7 days,and then subjecting the reaction mixture to the ordinary post-treatment.

Then, the protective groups R⁷ and R⁸ in the compound of the formula(VI) can be removed by the deprotection reaction in one step or pluralsteps depending on the kinds of the protective groups to obtain thecompound of the formula (I) according to the present invention. Thedeprotection reactions, which depend on the kinds of the protectivegroups R⁷ and R⁸ used, can be carried out according to the usual methodsgenerally known in the art. When either one or both of the protectivegroups can be removed under the acidic condition, a mineral acid such ashydrochloric acid, an organic acid such as oxalic acid, acetic acid orcitric acid, or a Lewis acid such as aluminium chloride is used. Whenthe protective groups is removed under a reducing condition, catalyticreduction with a variety of catalysts, or a metallic reducing agent suchas zinc or iron is used. When R⁷ is a silyl type protective group suchas a t-butyldiinethylsilyl group, a trimethylsilyl group or atriethylsilyl group, it can be easily removed with use of a fluorine ionreagent such as tetrabutylammonium fluoride. When R⁷ is anallyoxycarbonyl group and R⁸ is an allyl group, the protective groupscan be easily removed with use of a variety of palladium complexes suchas tetrakis(triphenylphosphine)palladium(0).

Process (2)

The compound of the formula (I) according to the present invention, inwhich R⁶ is not present, can be also prepared according to the followingreaction.

in which

R¹, R², R³, R⁴ and R⁵ have the same meanings as defined in the formula(I),

R⁸ has the same meaning as defined above,

R¹¹ represents a hydroxyl protecting group such as t-butyldimethylsilyl,trimethylsilyl, triethylsily or 4-nitrobenzyloxycarbonyl,

R¹² represents lower alkylcarbonyloxy such as t-butylcarbonyloxy,sec-butylcarbonyloxy, isopropylcarbonyloxy, arylcarbonyloxy such asbenzenecarbonyloxy, 2-chlorobenzenecarbonyloxcy, arylthio, preferably2-pyridylthio,

M represents Li, MgCl, MgBr or MgI.

The compound of the formula (VIII) in the scheme can be prepared by themethod described in PCT/JP97/04270.

In the first step, the compound of the formula (IX) can be convertedinto the compound of the formula (X) by the following method. When thereactant used is an acid halide such as pivaloyl chloride or2-chlorobenzoyl chloride, the compound of the formula (IX) can bereacted with one (1) equivalent or an excessive amount of the acidhalide in the presence of an organic base such as triethylamine,diisopropylethylamine, pyridine, 2,6-lutidine,diazabicyclo[2,2,2]undecene in a proportion of one (1) equivalent or anexcessive amount to the acid halide in an inert solvent such asacetonitrile, THF, dichloromethane or toluene, or a mixed solventthereof at a temperature of −50° C.-+50° C. for 10 minutes-24 hours, andthen subjected to the ordinary post-treatment to give the compound ofthe formula (X).

When the reactant used is a thiol-esterification agent, preferably2,2′-dipyridyl disulfide, the compound of the formula (IX) can bereacted with one (1) equivalent or an excessive amount of thethiol-esterification agent in the presence of a phosphine compound suchas triphenylphosphine or tributyl phosphine in a proportion of one (1)equivalent or an excessive amount to the thiol-esterification agent inan inert solvent such as acetonitrile, THF, dichloromethane or toluene,or a mixed solvent thereof at a temperature of −50° C.-+50° C. for 10minutes-24 hours, and then subjected to the ordinary post-treatment togive the compound of the formula (X).

In the second step, the compound of the formula (X) can be convertedinto the compound of the formula (XI) by the following method. Thecompound of the formula (XI) can be prepared by adding one (1)equivalent or an excessive amount of a solution of the compound of theformula (X) in an inert solvent such as diethyl ether or THF to thecompound of the formula (VIII) dissolved or suspended in an inertsolvent such as diethyl ether or THF, or by adding the compound of theformula (VIII) in an amount of less than one (1) equivalent dissolved orsuspended in an inert solvent such as diethyl ether or THF to thecompound of the formula (X) dissolved in an inert solvent such asdiethyl ether or THF, reacting the mixture at a temperature of −50°C.-+50° C. for 10 minutes-24 hours, and subjecting to the ordinarypost-treatment.

Then, in the third step, the compound of the formula (XI) can beconverted into the compound of the formula (XII) for example by thefollowing method. The compound of the formula (XII) can be prepared byreacting the compound of the formula (XI) dissolved in an inert solventsuch as benzene, toluene, xylene, THF or dioxane with a catalytic amountof an additive, preferably hydroquinone at a temperature of roomtemperature to refluxing temperature for 10 minutes-24 hours, andsubjected to the ordinary post-treatment.

The protective groups R⁸ and R¹¹ in the compound of the formula (VI) canbe removed by the deprotection reaction in one or more steps dependingon the kinds of the protective groups to obtain the compound of theformula (I) according to the present invention. The deprotectionreactions, which depend on the kinds of the protective groups R⁸ and R¹¹used, can be carried out according to the usual methods generally knownin the art. When either one or both of the protective groups can beremoved under the acidic condition, a mineral acid such as hydrochloricacid, an organic acid such as oxalic acid, acetic acid or citric acid,or a Lewis acid such as aluminium chloride is used. When the protectivegroups is removed under a reducing condition, catalytic reduction with avariety of catalysts, or a metallic reducing agent such as zinc or ironis used. When R¹¹ is a silyl type protective group such as at-butyldimethylsilyl group, a trimethylsilyl group or a triethylsilylgroup, it can be easily removed with use of a fluorine ion reagent suchas tetrabutylammonium fluoride. When R¹¹ is an allyoxycarbonyl group andR⁸ is an allyl group, the protective groups can be easily removed withuse of a variety of palladium complexes such astetrakis(triphenylphosphine)palladium(0).

The compound of the formula (I) thus obtained can be isolated andpurified by crystallization or by chromatography with a nonionicmacro-high porous resin, gel filtration with Sephadex or the like, orreverse phase silica gel column chromatography.

Process (3)

The compounds of the formula (I) in which R represents an esterhydrolizable in organisms can be prepared by converting the compoundsrepresented by the formula (I) into the ester derivatives.

in which

R¹, R², R³, R⁴, R⁵, and R have the same meanings as defined in theformula (I),

X represents a leaving group such as Cl, Br, I, —OSO₂CF₃, —OSO₂CH₃, or—OSO₂PhCH₃.

The ester derivatives can be prepared by reacting the compound of theformula (I) with an alkyl halide R10-X in the presence of one (1)equivalent or an excessive amount of a base at a temperature of −70-+50°C., preferably −30° C.-+20° C. for 10 minutes-24 hours.

The base usable in the reaction includes for example organic bases suchas diisopropylethylamine, diazabicyclo[2,2,2]undecene and 2,6-lutidine,and inorganic bases such as sodium hydroxide, potassium hydroxide,sodium hydrogen carbonate, potassium hydrogen carbonate, sodiumcarbonate, potassium carbonate and cesium carbonate.

The alkyl halide R¹⁰-X includes for example pivaloyloxymethyl iodide,1-(pivaloyloxy)ethyl iodide, isobu-tyryloxymethyl iodide,1-(isobutyryloxy)ethyl iodide, acetoxymethyl iodide, 1-(acetoxy)ethyliodide, (1-methyl cyclohexan-1-yl)carbonyloxy methyl iodide,1-(cyclohexyloxycarbonyloxy)ethyl iodide,1-[(cyclohexylmethoxy)carbonyloxy]ethyl iodide,1-(ethoxycarbonyloxy)ethyl iodide, cyclohexyloxycarbonyloxymethyliodide, 1-[(2-methylcyclohexan-1-yl)oxycarbonyloxy]ethyl iodide,cyclopentyloxycarbonyloxymethyl iodide, 1-(isopropyloxycarbonyloxy)ethyliodide, (1R, 2S,5R)-(1)-menthyloxycarbonyloxymethyl iodide,(1S,2R,5S)-(d)-menthyloxycarbonyloxymethyl iodide,1-(phenyloxycarbonyloxy)ethyl iodide, phenyloxycarbonyloxymethyl iodide,1-(cyclohexyloxycarbonyloxy)-N-propyl iodide,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide, 3-phthalidyl bromide,(Z)-2-(3-phthalidylidne)ethyl bromide, and the like.

The inert solvent usable in the reaction includes N,N-dimethylforamide,N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide,N-methylpyrrolidinone, N,N-dimethylimidazolidinoen, dimethylsulfoxide,sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran,1,4-dioxane, diethyl ether, anisole, dichloromethane,1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphorictriamide, methanol, and ethanol.

The ester derivatives thus obtained can be isolated and purified byprecipitation, crystallization, gel filtration with Sephadex, or silicagel chromatography.

Process (4)

The compound represented by the formula (I) in which R6 is present canbe prepared preferably by the following reaction.

in which

R¹, R², R³, R⁴, R⁵, and R⁶ have the same meanings as defined in theformula (I),

R⁷ and R⁸ have the same meanings as defined above,

Y represents a leaving group such as Cl, Br, I, —OSO₂CF₃, —OSO₂CH₃ or—OSO₂PhCH₃.

The compound of the formula (VI) can be prepared according to the methoddescribed above.

In the first step, the compound of the formula (VI) can be convertedinto the compound of the formula (VII) by the following method. Thecompound of the formula (VII) can be prepared by reacting the compoundof the formula (VI) with one (1) equivalent or an excessive amount ofthe compound R⁶-Y in the absence or presence of an inert solvent such asacetonitrile, acetone, tetrahydrofuran, dichloromethane, toluene,N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide aloneor in combination thereof at −80° C.-+60° C. for 15 minutes-1 week, andsubjected to the usual post-treatment. The compound of the formula R⁶-Yincludes for example methyl iodide, carbamoulmethyl iodide,2-fluoroethyl tri fluoro methanesulfonate, 2-hydroxyethyltrifluoromethanesulfonate, cyclopropylmethyl bromide, and methoxymethyliodide.

Then, the protective groups R⁷ and R⁸ in the compound of the formula(VII) can be removed by the deprotection reaction in one step or pluralsteps depending on the kinds of the protective groups to obtain thecompound of the formula (I) according to the present invention. Thedeprotection reactions, which depend on the kinds of the protectivegroups R⁷ and R⁸ used, can be carried out according to the usual methodsgenerally known in the art. When either one or both of the protectivegroups can be removed under the acidic condition, a mineral acid such ashydrochloric acid, an organic acid such as oxalic acid, acetic acid orcitric acid, or a Lewis acid such as aluminium chloride is used. Whenthe protective groups is removed under a reducing condition, catalyticreduction with a variety of catalysts, or a metallic reducing agent suchas zinc or iron can be used. When R⁷ is a silyl type protective groupsuch as t-butyldimethylsilyl, trimethylsilyl or triethylsilyl, it can beeasily removed with use of a fluorine ion reagent such astetrabutylammonium fluoride. When R⁷ is allyoxycarbonyl and R⁸ is allyl,the protective groups can be easily removed with use of a variety ofpalladium complexes such as tetrakis(triphenylphosphine)palladium(0).

The compound of the formula (I) thus obtained can be isolated andpurified by crystallization or by chromatography with a nonionicmacro-high porous resin, gel filtration with Sephadex or the like, orreverse phase silica gel column chromatography.

Process (5)

The compound of the formula (V) used in the above described reaction canbe prepared by the following method.

in which

R², R³, R⁴, and R⁵, either one of which is Mor R⁹ ₃SN, and the remainingthree, which may be the same or different, have the same meanings asdefined in the formula (I), that is, respectively represent hydrogen,halogen, nitro, cyano, lower alkyl, lower cycloalkyl, lower alkylthio,C₂₋₄ alkenyl, formyl, lower alkylcarbonyl, arylcarbonyl, aryl,

R⁹ represents lower alkyl, preferably N-butyl or methyl,

M represents Li, MgCl, MgBr or MgI, and

Z represents Cl, Br, I or —OSO₂CF₃.

The compound of the formula (VIII) used can be prepared according to themethod described in Japanese Patent Application No. 313922/1996.

The compound of the formula (VIII) can be converted into the compound ofthe formula (V) by the following method. The compound of the formula (V)can be prepared by reacting the compound of the formula (VIII) in aninert solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane,anisole, dimethoxyethane, dichloromethane or toluene solely or incombination thereof with R⁹ ₃SNZ in a proportion of one (1) equivalentor an excessive amount to the compound of the formula (VIII) at atemperature of −100° C.-+5° C. for 15 minutes-24 hours, and thensubjected to the usual post-treatment.

The compound of the formula (I) thus obtained can be isolated andpurified by crystallization or by chromatography with a nonionicmacro-high porous resin, gel filtration with Sephadex or the like, orreverse phase silica gel column chromatography.

Applications of the Compound/Pharmaceutical Composition

The compound according to the present invention has wide and stronganti-microbial activities against Gram-positive and Gram-negativebacteria, and exhibits strong anti-microbial activities against MRSA,PRSP, enterococci, influenza and β-lactamase producing bacteria as well.Furthermore, it has low toxicity and stable to DHP-1. Thus, the compoundaccording to the present invention can be used for the treatment ofinfections caused by various pathogenic bacteria in animals includinghuman beings.

The compound of the formula (I) in which R represents a grouphydrolyzable in organisms above all can be advantageously administeredorally because of its excellent oral absorption property.

The pharmaceutical composition comprising the compound according to thepresent invention and a pharmacologically acceptable salt and esterthereof as an effective ingredient can be administered orally orparenterally by the administration routes including intravenousinjection, intramuscular injection, or subcutaneous, rectal orpercutaneous administration to human begins and the other animals. Thus,the pharmaceutical composition comprising the compound according to thepresent invention as an effective ingredient can be formed intoappropriate dosage forms depending on its administration routes, andspecifically prepared primarily into any one of the preparation formsincluding injections such as intravenous injection and intramuscularinjection, preparations for oral administration such as capsules,tablets, granules, powder, pills, particulates, troches, preparationsfor rectal administration, and fatty suppositories. These preparationscan be prepared by the usual methods with ordinarily used excipients,fillers, binding agents, humidifiers, disintegrants, surface activeagents, lubricants, dispersants, buffers, storing agents, dissolutionaids, preservatives, flavoring agents, analgesic agents, stabilizingagents, and the like. Such non-toxic additives which can be used includefor example lactose, fructose, glucose, starch, gelatin, magnesiumcarbonate, synthetic magnesium silicate, talc, magnesium stearate,methylcellulose or a salt thereof, gum arabic, polyethylene glycol,syrup, petrolatum, glycerol, ethanol, propylene glycol, citric acid,sodium chloride, sodium sulfite, sodium phosphate, and the like. Thedosage amount is appropriately determined in consideration of the dosageroute, and the age, sex and condition of a patient, and the preparationmay be administered for the treatment of infections usually in an amountof about 25 mg-2000 mg, preferably 50 mg-1000 mg per day for adult inone or several portions.

EXAMPLE

The present invention is now described with reference to Examples andSynthetic Examples, but it is not limited thereto.

Preparation 1 3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and2-(-tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of imidazo[5,1-b]thiazole (248 mg) in anhydrous THF (4 ml)was cooled to −78° C. under the atmosphere of argon. A 1.6 N solution ofn-butyl lithium in n-hexane (1.31 ml) was added dropwise at an internaltemperature of −60° C.-−55° C. The reaction was stirred at the sametemperature for 1 hour, and it was further stirred for 40 minutes duringwhich the mixture was allowed to be warmed to room temperature. Thereaction mixture was diluted with 50 ml of a semi-saturated aqueousammonium chloride solution, and extracted with 50 ml of diethyl ether.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on silica gel (toluene:ethylacetate=1:1).

3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained in an amountof 221 mg from the fraction having Rf=0.7.

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.1 Hz), 1.22 (6H, m), 1.34 (6H, m), 1.59(6H, m), 6.63 (1H, s), 7.10 (1H, s), 7.92 (1H, s).

2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained in an amountof 270 mg from the fraction having Rf=0.5.

NMR (CDCl₃) δ: 0.92 (3H, t, 3=7.3 Hz), 1.16 (2H, m), 1.35 (2H, m), 1.58(2H, m), 7.02 (1H, s), 7.17 (1H, s), 7.95 (1H, s).

Preparation 2 2-(tri-n-butylstannyl)-3-methylimidazo[5,1-b]thiazole

A solution of 3-methylimidazo[5,1-b]thiazole (513.2 mg) in anhydrous THF(8 ml) was cooled to −78° C. under the atmosphere of argon, and a 1.6 Nsolution of n-butyl lithium in n-hexane (2.47 ml) was added dropwise.After the reaction was stirred at the same temperature for 1 hour, 1.06ml of tri-n-butylstannyl chloride was added, and the mixture was furtherstirred at the same temperature for 1 hour and then for 30 minutesduring which the mixture was allowed to be warmed to room temperature.The reaction mixture was diluted with 50 ml of a semi-saturated aqueousammonium chloride solution, and extracted with 50 ml of diethyl ether.The organic layer was dried over anhydrous magnesium sulfate, and thesolvent was then removed under reduced pressure. The residue thusobtained was purified by column chromatography on silica gel(hexane:ethyl acetate=1:1) to give2-(tri-n-butylstannyl)-3-methylimidazo[5,1-b]thiazole in a yield of 1.44g.

NMR (CDCl₃) δ: 0.84 (9H, t, J=7.3 Hz), 1.10 (6H, m), 1.28 (6H, m), 1.50(6H, m), 2.31 (3H, s), 6.96 (1H, s), 7.75 (1H, s). MS (PB(CH₄-CI)): 429(M⁺+H).

Preparation 3 5-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of 5-methylimidazo[5,1-b]thiazole (1.10 g) in THF (16 ml) wascooled to −78° C. under the atmosphere of argon, and a 1.6 N solution ofn-butyl lithium in n-hexane (5.24 ml) was added dropwise thereto at aninternal temperature of −70-−65° C. After the mixture was stirred at thesame temperature for 1 hour, 2.40 ml of ri-n-butylstannyl chloride wasadded, and the mixture was stirred at the same temperature for 1 hour,then for further two hours during which the mixture was allowed to bewarmed to −40° C. The reaction mixture was diluted with 100 ml of asemi-saturated aqueous ammonium chloride solution and extracted with 100ml of diethyl ether. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was then removed under reducedpressure. The residue thus obtained was purified by columnchromatography on silica gel (toluene:ethyl acetate=1:1) to give thetitle compound in a yield of 2.23 g.

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.2 Hz), 1.15(6H, m), 1.36(6H, m),1.57(6H, m), 2.57(3H, s), 6.88(1H, s), 6.93(1H, s).

Preparation 4 7-chloro-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-chloro-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 5,7-dichloroimidazo[5,1-b]thiazole, 5-chloroimidazo[5,1-b]thiazoleand 7-chloroimidazo[5,1-b]thiazole

To a solution of imidazo[5,1-b]thiazole (18.624 g) in dichloroethane(450 ml) was added 20.030 g of N-chlorosuccinimide, the mixture washeated in a bath at a temperature of 60-65° C. for 1 hour. After aircooling, insolubles were removed by filtration, and the solvent wasremoved under reduced pressure. The residue thus obtained was dissolvedin 3.0 l of ethyl acetate, and washed three times with 3.0 l ofdistilled water. After the organic layer was dried over anhydrousmagnesium sulfate and the magnesium sulfate was removed by filtration,the solvent was removed under reduced pressure. The solid product thusobtained was purified by column chromatography on silica gel (ethylacetate) to give 2.020 g of 5,7-dichloroimidazo[5,1-b]thiazole as a palebrown powder from the fraction of Rf=0.85.

NMR (CDCl₃) δ: 6.91 (1H, d, J=4.3 Hz), 7.28 (1H, d, J=4.3 Hz); MS (TSP):195 (M⁺+3H), 193 (M⁺+H).

Further, 5-chloroimidazo[5,1-b]thiazole was obtained as a pale brownpowder (2.550 g) from the fraction of Rf=0.7.

NMR (CDCl₃) δ: 6.87 (1H, d, J=4.3 Hz), 7.02 (1H, s), 7.29 (1H, d, J=4.3Hz). MS (TSP): 161 (M⁺+3H), 159 (M⁺+H).

Furthermore, 7-chloroimidazo[5,1-b]thiazole was obtained as a yellowishwhite plate (13.384 g) from the fraction of Rf=0.5.

NMR (CDCl₃) δ: 6.87 (1H, d, J=4.2 Hz), 7.38(1H, d, J=4.2 Hz), 7.87 (1H,s). MS (TSP): 161 (M⁺+3H), 159(M⁺+H).

b) 7-chloro-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-chloro-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

To 40 ml of THF was added 6.25 ml of a 1.6 N solution of n-butyl lithiumin n-hexane, and the mixture was cooled to −78° C. A solution of7-chloroimidazo[5,1-b]thiazole (1.59 g) in THF (40 ml) was addeddropwise at an internal temperature of −40° C. After the reactionmixture was stirred for 1 hour during which the temperature was raisedup to 0° C., 3.43 ml of tri-n-butylstannyl chloride was added, and themixture was stirred for 2 hours during which the temperature was raisedup to room temperature. The reaction mixture was diluted with 300 ml ofa semi-saturated aqueous ammonium chloride solution and extracted with300 ml of diethyl ether. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue thus obtained was purified by column chromatography onsilica gel (hexane:ethyl acetate=20:1-10:1-5:1-3:1).

As a low polar component,7-chloro-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained in ayield of 362 mg.

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.3 Hz), 1.22 (6H, m), 1.34 (6H, m), 1.54(6H, m), 6.63 (1H, s), 7.77 (1H, s).

Further, as a high polar component,7-chloro-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole was obtained in ayield of 2.78 g.

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.4 Hz), 1.16 (6H, m), 1.35 (6H, m), 1.58(6H, m), 7.11 (1H, s), 7.80 (1H, s).

Preparation 5 2-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The title compound was obtained in an amount of 2.67 g from 2.20 g of2-methylimidazo[5,1-b]thiazole in the same manner as in Preparation 3.

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.2 Hz), 1.24 (6H, m), 1.35 (6H, m), 1.54(6H, m), 2.35 (3H, s), 7.00 (1H, s), 7.83 (1H, s).

Preparation 65-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of 9 06 mg of 5-formylaminomethyl imidazo[5,1-b]-thiazole ina mixed solvent of 30 ml of THF and 6 ml of HMPA was cooled to −78° C.under the atmosphere of argon, and 10.9 ml of a 1.6 N solution ofn-butyl lithium/n-hexane was added dropwise at an internal temperatureof −70-−65° C. After the reaction mixture was stirred at the sametemperature for 1 hour, 1.63 ml of tri-n-butylstannyl chloride wasadded, and the mixture was further stirred at the same temperature for 1hour and for 2 hours during which the temperature was raised up to 0° C.100 ml of a semi-saturated aqueous ammonium chloride solution was addedto the reaction mixture, and extracted with 100 ml of diethyl ether. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on silica gel (hexane:ethylacetate=1:2) to give the title compound in an amount of 1.59 g.

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.4 Hz), 1.16 (6H, m), 1.35 (6H, m), 1.57(6H, m), 4.74 (2H, d, J=6.1 Hz), 6.90 (1H, s), 7.22 (1H, br. s), 7.37(1H, s), 8.28 (1H, s).

Preparation 73-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 3-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole

To an ice-cooled solution of 3.39 g of3-hydroxymethylimidazo[5,1-b]thiazole in 22 ml of DMF were added 1.95 gof imidazole and 3.81 g of t-butyldimethylsilyl chloride. After thereaction mixture was reacted at room temperature for 6 hours, it wasdiluted with 150 ml of ethyl acetate, and washed three times withsaline. The organic layer was dried over anhydrous magnesium sulfate,the solvent was removed under reduced pressure to give 5.83 g of3-(t-butyldi methylsilyloxy)methylimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.09 (6H, s), 0.88 (9H, s), 4.76 (2H, s), 6.60 (1H, s),7.07 (1H, s), 8.02 (1H, s).

b)3-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The title compound was obtained in an amount of 1.01 g from 548 mg of3-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole in the samemanner as in Preparation 3.

NMR (CDCl₃) δ: 0.15 (6H, s), 0.91 (9H, t, J=7.4 Hz), 0.93 (9H, s), 1.16(6H, m), 1.34 (6H, m), 1.56 (6H, m), 4.68 (2H, s), 7.01 (1H, s), 8.02(1H, s).

Preparation 85-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 5-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole

5-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole was obtained inan amount of 2.71 g from 1.54 g of 5-hydroxymethylimidazo[5,1-b]thiazolein the same manner as in Preparation 7-a).

NMR (CDCl₃) δ: 0.06 (6H, s), 0.89 (9H, s), 4.97 (2H, s), 6.79 (1H, d,J=4.3 Hz), 6.97 (1H, s), 7.55 (1H, d, J=4.3 Hz).

b)5-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

The title compound was obtained in an amount of 2.60 g from 1.34 g of5-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole in the samemanner as in Preparation 3.

NMR (CDCl₃) δ: 0.05 (6H, s), 0.89 (9H, s), 0.91 (9H, t, J=7.1 Hz), 1.14(6H, m), 1.35 (6H, m), 1.57 (6H, m), 4.96 (2H, s), 6.90 (1H, s), 7.32(1H, s).

Preparation 9 5-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand 5-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

5-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained asa low polar component in an amount of 114 mg from 167 mg of5-carbamoylimidazo[5,1-b]thiazole in the same manner as Preparation 6.

NMR (CDCl₃) δ: 0.87 (9H, t, J=7.4 Hz), 1.12 (6H, m), 1.32 (6H, m), 1.53(6H, m), 5.23 (1H, br. s), 6.88 (1H, s), 6.95 (1H, br. s), 7.19 (1H, s).

Further, 5-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]-thiazole wasobtained as a high polar component in an amount of 211 mg.

NMR (CDCl₃) δ: 0.91 (9H, t, J=7.4 Hz), 1.18 (6H, m), 1.35 (6H, m), 1.57(6H, m), 5.40 (1H, br. s), 6.90 (1H, br. s), 7.12 (1H, s), 8.12 (1H, s).

Preparation 10 7-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand 7-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-carboxylimidazo[5,1-b]thiazole

To an ice-cooled solution of 5.00 g of 7-iodoimidazo[5,1-b]-thiazole in150 ml of THF under the atmosphere of argon was added dropwise 20 ml ofa 1.0 N solution of N-ethylmagnesium bromide in THF. After the reactionmixture stirred at room temperature for 30 minutes, it was furtherstirred under bubbling carbon dioxide gas at room temperature for 20hours. The reaction mixture was concentrated under reduced pressure,diluted with 100 ml of water, and adjusted to pH 6.5 with 1 N HCl. Itwas purified with DIAION HP-20 (5-10% methanolic water) to give 3.31 gof 7-carboxylimidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 7.25 (1H, d, J=4.1 Hz), 7.86 (1H, d, J=4.1 Hz), 8.09(1H, s).

b) 7-carbamoylimidazo[5,1-b]thiazole

To a solution of 2.46 g of 7-carboxylimidazo[5,1-b]thiazole in 100 ml ofDMF were added 5.62 g of 1-hydroxybenzo-triazole and 5.62 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and themixture was stirred at room temperature for 1.5 hours, diluted with 15ml of a 3.5 N ammonia solution in ethanol, and further stirred at roomtemperature for 20 hours. The reaction mixture was concentrated underreduced pressure, diluted with 200 ml of an aqueous potassium carbonatesolution to adjust pH to 10.4, and extracted ten times withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuethus obtained was purified by column chromatography on silica gel(dichloromethane:methanol=30:1) to give7-carbamoylimidazo[5,1-b]thiazole in a yield of 1.83 g.

NMR (CDCl₃) δ: 5.36 (1H, br. s), 6.77 (1H, br. s), 7.04 (1H, d, J=4.1Hz), 7.50 (1H, d, J=4.1 Hz), 7.94 (1H, s).

c) 7-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

7-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained asa low polar component in an amount of 360 mg from 1.23 g of7-carbamoylimidazo[5,1-b]thiazole in the same manner as Preparation 6.

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.3 Hz), 1.24 (6H, m), 1.35 (6H, m), 1.55(6H, m), 5.38 (1H, br. s), 6.78 (1H, brs. s), 6.82 (1H, s), 7.83(1H, s).

Further, 7-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained as a high polar component in an amount of 420 mg.

NMR (CDCl₃) δ: 0.91 (9H, t, J=7.2 Hz), 1.17 (6H, m), 1.35 (6H, m), 1.58(6H, m), 5.35 (1H, br. s), 6.75(1H, br. s), 7.23(1H, s), 7.88(1H, s).

Preparation 11 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-cyanoimidazo[5,1-b]thiazole

To a suspension of 997 mg of 7-carbamoylimidazo[5,1-b]-thiazole in 80 mlof dichloromethane were add under ice-cooling 7.28 ml ofN,N-diisopopylethylamine and 2.23 ml of phosphorus oxychloride. Afterthe reaction mixture was stirred at the same temperature, it was pouredonto ice-water, adjusted pH to 7.5 with aqueous sodium hydrogencarbonate, and extracted three times with dichloromethane. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby column chromatography on silica gel (dichloromethane:methanol=15:1)to give 871 mg of 7-cyanoimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 7.08 (1H, d, J=4.2 Hz), 7.56 (1H, d, J=4.2 Hz), 8.01 (1H,s).

b) 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of 903 mg of 7-cyanoimidazo[5,1-b]thiazole in 35 ml of THFwas cooled to −78° C. under the atmosphere of argon, and 6.36 ml of a1.0 N solution of lithium bistrimethylsilylamide in THF was addeddropwise at an internal temperature of −70-−65° C. After the reactionmixture was stirred at the same temperature for 1 hour, 1.81 ml oftri-n-butylstannyl chloride was added, and the mixture was stirred atthe same temperature for 1 hour. The reaction mixture was diluted with100 ml of a semi-saturated aqueous ammonium chloride solution andextracted with 100 ml of ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue thus obtained was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:1) to give thetitle compound in a yield of 795 mg.

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.3 Hz), 1.19 (6H, m), 1.36 (6H, m), 1.58(6H, m), 7.26 (1H, s), 7.93 (1H, s).

Preparation 12 7-ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-vinylimidazo[5,1-b]thiazole

To a solution of 5.0 g of 7-iodoimidazo[5,1-b]thiazole in 40 ml of NMPwere added under the atmosphere of argon 550 mg oftris(dibenzilideneacetone) dipalladium, 558 mg of tri-2-furyl phosphine,and 6.42 ml of tri-n-butylvinyltin, and the mixture was reacted at 70°C. for 1.5 hours, and at 80° C. for 2 hours. The reaction mixture waspoured into a mixture of 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of a saturated saline, and extracted twotimes with 200 ml of ethyl acetate. The organic layers were combined,washed three times with 200 ml of saline, dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuethus obtained was purified by column chromatography on silica gel(dichloromethane:ethyl acetate=15:1) to give7-vinylimidazo[5,1-b]thiazole in an amount of 1.99 g.

NMR (CDCl₃) δ: 5.27 (1H, d), 5.41 (1H, d), 6.80 (1H, dd), 6.91 (1H, d),7.42 (1H, d), 7.98 (1H, s).

b) 7-ethylimidazo[5,1-b]thiazole

To a solution of 5.0 g of 7-vinylimidazo[5,1-b]thiazole in 40 ml ofethanol and 8 ml of water was added 2.0 g of 10% Pd-C, and the mixturewas stirred under the atmosphere of hydrogen at room temperatureovernight. The catalyst was removed by filtration, and the filtrate wasconcentrated to a small volume. The concentrate was diluted with 10 mlof a saturated aqueous sodium hydrogen carbonate solution, and extractedwith 100 ml of ethyl acetate. The organic layer was washed with aqueoussaline and dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby column chromatography on silica gel (dichloromethane:ethylacetate=3:2) to give 1.27 g of 7-ethylimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.33 (3H, t), 2.76 (2H, q), 6.76 (1H, d), 7.32 (1H, d),7.91 (1H, s).

c) 7-ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

In the same manner as in Preparation 3, 1.50 g of7-ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole as a low polarcomponent from 1.27 g of 7-ethylimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.90 (9H, t), 1.1-1.5 (15H, m), 1.5-1.7 (6H, m), 2.76(2H, q), 6.57 (1H, s), 7.82 (1H, s).

Further, 1.32 g of 7-ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]-thiazolewas obtained as a high polar component.

NMR (CDCl₃) δ: 0.92 (9H, t), 1.1-1.5 (15H, m), 1.5-1.7 (6H, m), 2.75(2H, q), 7.09 (1H, s), 7.86 (1H, s).

Preparation 137-(1-t-butyldimethylsilyloxy)ethyl-3-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazoleand7-(1-t-butyldimethylsilyloxy)ethyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole

a) 7-(1-hydroxy)ethylimidazo[5,1-b]thiazole

A solution of 3.043 g of 7-formyl[5,1-b]thiazole in 60 ml of of dry THFwas cooled to −58° C. under the atmosphere of argon. To this solutionwas added dropwise 23 ml of a 0.92 M methylmagnesium bromide solution inTHF under stirring at a temperature of −60-−55° C. over 10 minutes, themixture was further stirred at the same temperature for 10 minutes, thendirectly warmed slowly to room temperature with stirring for further 2days. The reaction mixture was diluted with 50 ml of a saturated aqueousammonium chloride-solution, subjected to salting out, and extracted fourtimes with 150 ml of ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate, filtered, and the solvent was removedunder reduced pressure. The yellow oil thus obtained was purified bycolumn chromatography on silica gel (dichloromethane:methanol=95:5) togive 7-(1-hydroxy)ethylimidazo[5,1-b]thiazole as light yellow crystalsin a yield of 2.164 g.

NMR (CDCl₃) δ: 1.62 (3H, d, J=6.5 Hz), 2.95 (1H, br. s), 5.08 (1H, q,J=6.5 Hz), 6.82 (1H, d, J=4.3 Hz), 7.37 (1H, d, J=4.3 Hz), 7.94 (1H, s).MS (TSP): 169(M⁺+H).

b) 7-(1-t-butyldimethyloxy)ethylimidazo[5,1-b]thiazole

To a solution of 2.086 g of 7-(1-hydroxy)ethylimidazo[5,1-b]thiazole in12.4 ml of dry DMF were added under ice-cooling 1.098 g of imidazole and2.150 g of t-butyldimethylsilyl chloride, and the mixture wasimmediately stirred under the atmosphere of argon for 1 hour. Thereaction mixture was diluted with 100 ml of ethyl acetate, and washedthree times with 50 ml of semi-saturated aqueous saline. The organiclayer was dried over anhydrous magnesium sulfate, filtered, and thesolvent was removed under reduced pressure. The yellow oil thus obtainedwas purified by column chromatography on silica gel (dichloromethanealone—dichloromethane:methanol=96:4) to give 3.440 g of7-(1-t-butyldimethyloxy)ethylimidazo[5,1-b]thiazole as milk whitecrystals in a yield of 3.440 g.

NMR (CDCl₃) δ: 0.09 (3H, s), 0.12 (3H, s), 0.95 (9H, s), 1.52 (3H, d,J=6.3 Hz), 5.10 (1H, q, J=6.3 Hz), 6.77 (1H, d, J=4.3 Hz), 7.33 (1H, d,J=4.3 Hz), 7.90 (1H, s). MS (TSP): 283(M⁺+H).

c)7-(1-t-butyldimethylsilyloxy)ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand7-(1-t-butyldimethylsilyloxy)ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

In the same manner as in Preparation3,7-(1-t-butyldimethylsilyloxy)ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazolewas obtained as a low polar component in a yield of 1.38 g from 1.67 gof 7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.08 (3H, s), 0.12 (3H, s), 0.89 (9H, t, J=7.3 Hz), 0.95(9H, s), 1.20 (6H, m), 1.34 (6H, m), 1.54 (9H, m), 5.10 (1H, q, J=6.3Hz), 6.59 (1H, s), 7.82 (1H, s).

Further,7-(1-t-butyldimethylsilyloxy)ethyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazolewas obtained as a high polar component in a yield of 812 mg.

NMR (CDCl₃) δ: 0.09 (3H, s), 0.12 (3H, s), 0.91 (9H, t, J=7.4 Hz), 0.95(9H, s), 1.13 (6H, m), 1.34 (6H, m), 1.55 (9H, m), 5.08 (1H, q, J=6.3Hz), 7.09 (1H, s), 7.85 (1H, s).

Preparation 14 7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole,7-methoxyiminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer), 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole, and7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer)

a) 5-formylimidazo[5,1-b]thiazole and 7-formylimidazo[5,1-b]thiazole

To the mixture of 15.48 ml of DMF and 80 ml of dichloromethane was addeddropwise a solution of 18.32 ml of phosphorus oxychloride in 80 ml ofdichloromethane under ice-cooling. The mixture was reacted at roomtemperature for 30 minutes, and a solution of imidazo[5,1-b]thiazole in40 ml of chloromethane was added dropwise. After heating under refluxfor 2.5 hours, the reaction mixture was poured onto ice, adjusted to pH9.8 with a 5 N aqueous sodium hydroxide solution, extracted five timeswith 200 ml of dichloromethane, dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure. The residue thusobtained was purified by column chromatography on silica gel(dichloromethane:ethyl acetate=5:1-ethyl acetatealone—dichloromethane:methanol=10:1). As a low polar component,5-formylimidazo[5,1-b]thiazole was obtained in a yield of 495 mg.

NMR (CDCl₃) δ: 7.18 (1H, d, J=4.1 Hz), 7.46 (1H, s), 8.46 (1H, d, J=4.1Hz), 9.76 (1H, s).

Further, as a high polar component, 7-formylimidazo[5,1-b]thiazole wasobtained in a yield of 2.37 g.

NMR (CDCl₃) δ: 7.17 (1H, d, J=4.1 Hz), 7.60 (1H, d, J=4.1 Hz), 8.07 (1H,s), 9.93 (1H, s).

b) 7-methoxyiminomethylimidazo[5,1-b]thiazole (high polar geometricalisomer) and 7-methoxyiminomethylimidazo[5,1-b]thiazole (low polargeometrical isomer)

To a suspension of 249 mg of 7-formylimidazo[5,1-b]thiazole in 10 ml ofethanol were added 219 mg of o-methylhydroxylamine hydrochloride and2.67 ml of a 1N sodium hydroxide solution. The reaction mixture wasstirred at room temperature for 20 hours, concentrated, then dilutedwith 50 ml of water, and extracted with dichloromethane. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby column chromatography on silica gel (dichloromethane:ethylacetate=1:1) to give 7-methoxyiminomethylimidazo[5,1-b]thiazole (lowpolar geometrical isomer) in a yield of 164 mg from the low polarityfraction.

NMR (CDCl₃) δ: 3.96 (3H, s), 7.01 (1H, d, J=4.1 Hz), 7.48 (1H, d, J=4.1Hz), 8.02 (1H, s), 8.24 (1H, s).

Further, 7-methoxyiminomethylimidazo[5,1-b]thiazole (high polargeometrical isomer) was obtained in a yield of 71 mg from the low polarfraction.

NMR (CDCl₃) δ: 4.40 (3H, s), 6.90 (1H, d, J=4.4 Hz), 7.43 (1H, d, J=4.4Hz), 7.46 (1H, s), 7.94 (1H, s).

c) 7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole,7-methoxyiminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer), 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole, and7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]-tiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer)

In the same manner as in Preparation 3,7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained in anamount of 67 mg from the fraction having Rf=0.8 (n-hexane:ethylacetate=3:1) starting from 1.17 g of7-methoxyiminomethylimidazo[5,1-b]thiazole (high polar geometricalisomer).

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.2 Hz), 1.26 (6H, m), 1.35 (6H, m), 1.57(6H, m), 6.80 (1H, s), 7.87 (1H, s).

Further,7-methoxyiminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer) was obtained in a yield of 1.26 g from the fraction havingRf=0.6 (n-hexane:ethyl acetate=3:1).

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.4 Hz), 1.22 (6H, m), 1.34 (6H, m), 1.56(6H, m), 3.98 (3H, s), 6.71 (1H, s), 7.46 (1H, s), 7.84 (1H, s).

Furthermore, 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained in a yield of 150 mg from the fraction having Rf=0.4(n-hexane:ethyl acetate=3:1).

The NMR data of this compound were well agreed with those obtained inPreparation 11.

Furthermore,7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a high polaroxime isomer) was obtained in a yield of 980 mg from the fraction havingRf=0.2 (n-hexane:ethyl acetate=3:1).

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.3 Hz), 1.16 (6H, m), 1.36 (6H, m), 1.58(6H, m), 4.00 (3H, s), 7.18 (1H, s), 7.45 (1H, s), 7.89 (1H, s).

Preparation 15 7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole,7-methoxyimino-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(stereoisomer derived from a raw material which is a low polar oximeisomer), 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole, and7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(stereoisomer derived from a raw material which is a low polar oximeisomer)

In the same manner as in Preparation 3,7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained in ayield of 288 mg from the fraction having Rf=0.8 (n-hexane:ethylacetate=3:1) starting from 1.47 g of7-methoxyiminomethylimidazo[5,1-b]thiazole (low polar geometricalisomer) described in Preparation 14-b).

The NMR data of this compound were well agreed with those obtained inPreparation 14.

Further,7-methoxyiminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(geometrical isomer derived from a raw material which is a low polaroxime isomer) was obtained in a yield of 1.68 g from the fraction havingRf=0.7 (n-hexane:ethyl acetate=3:1).

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.4 Hz), 1.24 (6H, m), 1.35 (6H, m), 1.55(6H, m), 3.96 (3H, s), 6.81 (1H, s), 7.92 (1H, s), 8.25 (1H, s).

Furthermore, 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained in a yield of 353 mg from the fraction having Rf=0.4(n-hexane:ethyl acetate=3:1).

The NMR data of this compound were well agreed with those obtained inPreparation 11.

Furthermore,7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1b]thiazole(geometrical isomer derived from a raw material which is a low polaroxime isomer) was obtained in a yield of 704 mg from the fraction havingRf=0.3 (n-hexane:ethyl acetate=3:1).

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.3 Hz), 1.18 (6H, m), 1.35 (6H, m), 1.57(6H, m), 3.97 (3H, s), 7.22 (1H, s), 7.96 (1H, s), 8.23 (1H, s).

Preparation 167-formylaminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

Using 0.72 g of 7-formylaminomethyl imidazo[5,1-b]thiazole,7-formylaminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained in a yield of 0.99 g as a low polar component, and7-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in ayield of 0.64 g as a high polar component in the same manner as inPreparation 1.

7-formylaminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

NMR (CDCl₃) δ: 0.90 (9H, t, J=7.1 Hz), 1.22 (6H, m), 1.34 (6H, m), 1.55(6H, m), 4.58 (2H, d, J=5.6 Hz), 6.32 (1H, br s), 6.63 (1H, s), 7.85(1H, s), 8.27 (1H, s).

7-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.3 Hz), 1.16 (6H, m), 1.35 (6H, m), 1.58(6H, m), 4.56 (2H, d, J=6.4 Hz), 6.51 (1H, br s), 7.13 (1H, s), 7.89(1H, s), 8.38 (1H, s).

Preparation 177-(t-butyldimethylsilyloxy)methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand7-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole

a) 7-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole

To a solution of 2.42 mg of 7-hydroxymethylimidazo[5,1-b]thiazole in 15ml of DMF were added under ice-cooling 1.4 g of imidazole and 2.73 g oft-butyldimethylsilylchloride, and the mixture was stirred at the sametemperature for 2 hours. DMF was removed under reduced pressure, and theresidue was extracted two times with ethyl acetate. The organic layerwas washed two times with a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate, and removed under reducedpressure to give 7-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazolein a yield of 4.02 g.

NMR (CDCl₃) δ: 0.13 (6H, s), 0.97 (9H, s), 4.88 (2H, s), 6.78 (1H, d,J=4.1 Hz), 7.34 (1H, d, J=4.1 Hz), 7.92 (1H, s).

b)7-(t-butyldimethylsilyloxy)methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand7-(-t-butyldimethylsilyloxy)methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole

A solution of 2.25 g of7-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole in 5 ml of THFwas cooled to −78° C. under the atmosphere of argon, and 5.3 ml of a 1.6N solution of n-butyl lithium in n-hexane was added dropwise at the sametemperature. After the reaction mixture was stirred for 2 hours, 2.24 mlof tri-n-butyl-stannyl chloride was added, and the resulting mixture wasstirred at the same temperature for 1 hour, and for 3 hours during whichthe temperature was raised up to 0° C. The reaction mixture was dilutedwith a saturated sodium chloride solution, and extracted two times withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuethus obtained was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1).

7-(t-butyldimethylsilyloxy)methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazolewas obtained in a yield of 1.54 g from the fraction having Rf=0.6(hexane:ethyl acetate=1:1).

NMR (CDCl₃) δ: 0.01 (6H, s), 0.76 (9H, t, J=7.1 Hz), 0.83 (9H, s),1.04-1.26 (12H, m), 1.38-1.49 (6H, m), 4.74 (2H, s), 6.47 (1H, s), 7.71(1H, s). MS (TSP): 559(M⁺+3H), 557(M⁺+H).

Further,7-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazolewas obtained in a yield of 1.67 g from the fraction having Rf=0.3.

NMR (CDCl₃) δ: 0.01 (6H, s), 0.78 (9H, t, J=7.1 Hz), 0.83 (9H, s),1.00-1.07 (6H, m), 1.18-1.30 (6H, m), 1.40-1.50 (6H, m), 4.73 (2H, s),6.97 (1H, s), 7.73 (1H, s). MS (TSP): 559(M⁺+3H), 557(M⁺+H).

Preparation 187-(N-methylcarbamoyl)-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-(N-methylcarbamoyl)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-(N-methylcarbamoyl)imidazo[5,1-b]thiazole

To a solution of 2.06 g of 7-carboxylimidazo[5,1-b]thiazole in 90 ml ofDMF were added 4.98 g of 1-hydroxybenzotriazole and 4.72 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and themixture was stirred at room temperature for 10 minutes. Then, 18.5 ml ofa 2N solution of methylamine in THF was added, and the mixture wasstirred at the same temperature 18 hours. The reaction mixture wasdiluted with water and adjusted to pH=9.6 with powdery potassiumcarbonate, and extracted five times with dichloromethane and five timeswith ethyl acetate. The combined organic layer was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue thus obtained was purified by column chromatography onsilica gel (dichloromethane:methanol=10:1) followed by Sephadex LH-20(dichloromethane:methanol=1:1) to give 0.80 g of7-(N-methylcarbamoyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 3.01 (3H, d, J=5.0 Hz), 6.90 (1H, br, s), 7.00 (1H, d,J=4.1 Hz), 7.48 (1H, d, J=4.1 Hz), 7.92 (1H, s). MS (EI): 181 (M⁺).

b) 7-(N-methylcarbamoyl)-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazoleand 7-(N-methylcarbamoyl)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of 716 mg of 7-(N-methylcarbamoyl)imidazo[5,1-b]thiazole in35 ml of THF was cooled to −78° C. under the atmosphere of argon, and6.0 ml of a 1.6 N solution of n-butyl lithium in n-hexane was addeddropwise at the same temperature. After the reaction mixture was stirredfor 1.5 hours, 1.40 ml of tri-n-butylstannyl chloride was added, and themixture was stirred for 5 hours during which the temperature was raisedup to −40° C. The reaction mixture was diluted with water, and extractedtwo times with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue thus obtained was purified by column chromatography o)n)silica gel (hexane:ethyl acetate=3:1).

7-(N-methylcarbamoyl)-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained in a yield of 441 mg from the fraction havingRf=0.5(hexane:ethyl acetate=1:1).

NMR (CDCl₃) δ: 0.83 (9H, t, J=7.3 Hz), 1.16-1.32 (12H, m), 1.44-1.61(6H, m), 2.94 (3H, d, J=5.0 Hz), 6.72 (1H, s), 6.70-6.80 (1H, m), 7.73(1H, s).

Further, 702 mg of7-(N-methylcarbamoyl)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained from the fraction having Rf=0.4.

NMR (CDCl₃) δ: 0.91 (9H, t, J=7.3 Hz), 1.15-1.40 (12H, m), 1.55-1.60(6H, m), 3.00 (3H, d, J=5.2 Hz), 6.80-6.88 (1H, m), 7.21 (1H, s), 7.85(1H, s). MS (APCI): 472 (M⁺+3H), 470 (M⁺+H).

Preparation 19 7-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A 1.66 N solution of n-butyl lithium/n-hexane (15.8 ml) dissolved in dryTHF (75 ml) cooled to −69° C. under the atmosphere of argon, and asolution of 3.455 g of 7-methylimidazo[5,1-b]thiazole in 50 ml of THFwas added dropwise under stirring at −69-−66° C. over 20 minutes. Thereaction mixture was further stirred at the same temperature 10 minutes,and 7.8 ml of tri-n-butylstannyl chlorideat was added dropwise at thesame temperature over the period of 10 minutes. Then, The reactionmixture was gradually warmed to room temperature, and stirred for 15hours. The reaction mixture was diluted with 100 ml of a semi-saturatedaqueous saline, and extracted with 250 ml of ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, filtered, and thesolvent was removed by distillation. The oil thus obtained was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=2:1-1:1).

7-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole was obtained as ayellow oil in a yield of 4.760 g from the fraction having Rf=0.5(n-hexane:ethyl acetate=2:1).

NMR (CDCl₃) δ: 0.89 (9H, t, J=7.2 Hz), 1.17-1.23 (6H, m), 1.27-1.40 (6H,m), 1.50-1.65 (6H, m), 2.36 (3H, s), 6.57 (1H, s), 7.83 (1H, s). MS(TS):429(M⁺+3H), 427(M⁺+H).

Further, 7-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole wasobtained as a yellow oil in a yield of 3.653 g from the fraction havingRf=0.2 (n-hexane:ethyl acetate=2:1).

NMR (CDCl₃) δ: 0.91 (9H, t, J=7.2 Hz), 1.11-1.17 (6H, m), 1.19-1.41 (6H,m), 1.53-1.63 (6H, m), 2.34 (3H, s), 7.08 (1H, s), 7.85 (1H, s). MS(TS):429(M⁺+3H), 427(M⁺+H).

Preparation 20 5,7-dimethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 2-(1-acetylamino)ethylthiazole

To a solution of 3.40 g of 2-(1-amino)ethylthiazole in 53 ml of THF wasadded 2.6 ml of dry pyridine, and the mixture was cooled to −70° C.under the atmosphere of argon. To the mixture was added dripwise 2.6 mlof acetic anhydride over a period of 5 minutes, and further stirred onan ice bath for 1 day. The reaction mixture was diluted with 40 ml of 5%aqueous sodium hydrogen carbonate, and extracted once with 200 ml andthrice with 100 ml of dichloromethane. The combined organic layer wasdried over anhydrous sodium sulfate, filtered, and the solvent wasremoved under reduced pressure. The solid residue thus obtained waspurified by column chromatography on silica gel (ethyl acetatealone—ethyl acetate:methanol=96:4) to give2-(1-acetyl-amino)ethylthiazole as a milk white powder in a yield of3.456 g.

NMR (CDCl₃) δ: 1.62 (3H, d, J=6.9 Hz), 2.05 (3H, s), 5.44 (1H, quintet,J=6.9 Hz), 6.43 (1H, br. s), 7.28 (1H, d, J=3.3 Hz), 7.71 (1H, d, J=3.3Hz). MS (TSP): 171(M⁺+H).

b) 5,7-dimethylimidazo[5,1-b]thiazole

To 3.392 g of 2-(1-acetylamino)ethylthiazole were added 17 ml of drytoluene and 9 ml of phosphorus oxychloride, and the mixture was stirredat a bath temperature of 90° C. for 75 minutes. The reaction mixture wascooled to room temperature, diluted with 30 ml of distilled water and100 ml of dichloromethane, neutralized under stirring with potassiumcarbonate, salted out, and the organic layer was separated. The aqueouslayer was further extracted with 50 ml of dichloromethane. The combinedorganic layer was dried over anhydrous potassium carbonate. The crudefine crystalline product thus obtained was purified by columnchromatography on silica gel (dichloromethane:methanol=98:2) to give5,7-dimethylimidazo[5,1-b]thiazole as milk white crystals in a yield of2.787 g.

NMR (CDCl₃) δ: 2.30 (3H, s), 2.53 (3H, s), 6.71 (1H, d, J=4.2 Hz), 7.12(1H, d, J=4.2 Hz). MS (TSP): 153(M⁺+H).

c) 5,7-dimethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

To 50 ml of anhydrous THF cooled to −65° C. under the atmosphere ofargon was added 10.9 ml of a 1.63 N n-butyl lithium/n-hexane solution,and a solution of 2.564 g of 5,7-dimethylimidazo[5,1-b]thiazole in 17 mlof anhydrous THF was further added dropwise at −64-−60° C. over a periodof 15 minutes. The reaction mixture was then stirred at the sametemperature for 80 minutes. After 5.0 ml of tri-n-butylstannyl chloridewas added dropwise to the mixture at a temperature of −63-−58° C. over aperiod of 10 minutes, it was warmed to −30° C., and further stirred for110 minutes. The reaction mixture was diluted with 100 ml ofsemi-saturated aqueous saline, extracted with 150 ml of ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtered, andthe solvent was removed under reduced pressure. The oil thus obtainedwas purified by column chromatography on silica gel (n-hexane:ethylacetate=1:1-−1:2) to give the title compound as a light orange oil in ayield of 6.164 g.

NMR (CDCl₃) δ: 0.92 (9H, t, J=7.2 Hz), 1.10-1.17 (6H, m), 1.30-1.42 (6H,m), 1.53-1.65 (6H, m), 2.29 (3H, s), 2.53 (3H, s), 6.85 (1H, s). MS(TSP): 443, 441, 439.

Preparation 217-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-methoxymethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

a) 7-methoxymethylimidazo[5,1-b]thiazole

To a solution of 2.0 g of 7-hydroxymethylimidazo[5,1b]thiazole in 25 mlof DMF was added under ice-cooling 600 mg of sodium hydride (60% in oil)under the atmosphere of argon. White insolubles were produced in a shorttime. When stirring becomes difficult, DMF was added. After 30 minutes,2.0 g of iodomethane was added to dissolve the precipitate. Afteradditional stirring for 1 hour, 200 ml of ethyl acetate and 100 ml ofsemi-saturated aqueous saline were added, and the mixture was stirredand separated. The organic layer was washed three times with 100 ml ofsemi-saturated aqueous saline, dried over anhydrous magnesium sulfate,and purified by column chromatography on silica gel and on SephadexLH-20 to give 1.41 g of 7-methoxymethylimidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 3.43 (3H, s), 4.59 (2H, s), 6.83 (1H, d, J=4.2 Hz), 7.38(1H, d, J=4.2 Hz), 7.96 (1H, s).

b) 7-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole and7-methoxymethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole

A solution of 925 mg of 7-methoxymethylimidazo[5,1-b]thiazole inanhydrous THF was cooled to −70° C. under the atmosphere of argon and3.54 ml of a 1.6 N n-butyl lithium/n-hexane solution was slowly added,and the mixture was stirred for 1 hour. To the reaction mixture wasslowly added a solution of 1.88 g of tri-n-butylstannyl chloride in 2 mlof anhydrous THF, and the mixture was stirred for further 1.5 hours.After the addition of 100 ml of ethyl acetate, the solvent was removedby distillation to concentrate the mixture to a total volume of about 1ml. Purification by silica gel chromatography gave 896 mg of7-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole from a lowpolar fraction eluted with dichloromethane:ethyl acetate=4:1.

NMR (CDCl₃) δ: 0.80-1.80 (27H, m), 3.42 (3H, s), 4.58 (2H, s), 6.63 (1H,s), 7.87 (1H, s).

Further, purification by column chromatography on silica gel gave 712 mgof 7-methoxymethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole from ahigh polar fraction eluted with dichloromethane:ethyl acetate 1:1-1:4.

NMR (CDCl₃) δ: 0.80-1.80 (27H, m), 3.42 (3H, s), 4.57 (2H, s), 7.13 (1H,s), 7.90 (1H, s).

Preparation 22 7-(N,N-dimethylcarbamoyl)-3-(tri-n-butylstannyl)imidazothiazole and7-(N,N-dimethylcarbamoyl)-2-(tri-n-butylstannyl)imidazothiazole(approximately 1:1 mixture)

a) 7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazole

To a solution of 1.71 g of 7-carboxylimidazo[5,1-b]thiazole in 34 ml ofDMF was added 5.45 g of 1-hydroxybenzotriazole and 6.80 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at roomtemperature under the atmosphere of argon, and the mixture was stirredfor 1 hour. To the reaction mixture was added under ice-cooling 20 ml ofa saturated dimethylamine solution in THF, and the mixture was stirredat room temperature overnight. The reaction mixture was diluted with 300ml of dichloromethane and 180 ml of water, stirred vigorously andseparated. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was removed under reduced pressure. The residue thusobtained was purified by column chromatography on silica gel(dichloromethane:methanol=94:6-90:10) to give 663 mg of7-(N,N-dimethyl-carbamoyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 3.0-3.8 (6H, m), 6.99 (1H, d, J=4.2 Hz), 7.47 (1H, d,J=4.2 Hz), 7.93 (1H, s).

b) 7-(N,N-dimethylcarbamoyl)-3-(tri-n-butylstannyl)imidazothiazole and7-(N,N-dimethylcarbamoyl)-2-(tri-n-butyl-tannyl)imidazothiazole(mixture)

A solution of 660 mg of 7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazolein 30 ml of anhydrous THF was cooled to −55° C. under the atmosphere ofargon. 2.4 ml of a 1.6 N solution of n-butyl lithium/n-hexane was slowlyadded, and the mixture was stirred for 1 hour. A solution of 1.30 g oftri-n-butylstannyl chloride in 10 ml of anhydrous THF was slowly added,and the reaction mixture was stirred for 1 hour. The reaction mixturewas diluted with 120 ml of ethyl acetate and 30 ml of water, stirred andseparated. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was removed to concentrate the organic layer to a totalvolume of about 1 ml. The residue thus obtained was purified bychromatography on silica gel (hexane:ethyl acetate=1:1) to give 980 mgof the title compound as an approximately 1:1 mixture.

NMR (CDCl₃) δ: 0.7-1.7 (27H, m), 2.9-3.9 (6H, br. s), 6.81 (0.5H, s,3-stannyl derivative), 7.21 (0.5H, s, 2-stannyl derivative), 7.84 (0.5H,s, 3-stannyl derivative), 7.88 (0.5H, s, 2-stannyl derivative).

Example 1(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 7.24 g of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylatein 150 ml of dry acetonitrile was added dripwise 6.97 ml ofN,N-diisopropylethylamine, followed by 3.70 ml of anhydroustrifluo-methanesulfonic acid under the atmosphere of argon at −15° C.After the reaction mixture was stirred at the same temperature for 30minutes, it was diluted with 500 ml of ethyl acetate, and washedsequentially with semi-saturated aqueous saline, a mixture ofsemi-saturated aqueous saline and 1N hydrochloric acid (pH 1.1), amixture of semi-saturated aqueous saline and saturated aqueous sodiumhydrogen carbonate (pH 8.9), and saturated aqueous saline. After dryingover anhydrous magnesium sulfate, the reaction mixture was filtered,diluted with 40 ml of dry N-methylpyrrolidine, and ethyl acetate andacetonitrile was removed under reduced pressure. The residue was mixedwith a solution of 553 mg of tris(dibenzylideneacetone)dipalladium (0),558 mg of tri-2-furylphosphine, 9.14 g of2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 10 ml of dryN-methylpyrrolidinone, and 5.47 g of zinc chloride, and the mixture wasstirred under the atmosphere of argon at 50° C. for 1 hour. The solventwas evaporated under reduced pressure, the concentrate was diluted with150 ml of diethyl ether, and the supernatant was separated. Theprocedure was repeated two more times, and the residue thus obtained wasdiluted with 400 ml of ethyl acetate and 80 ml of water. The insolubleswere collected by filtration, and washed with ethyl acetate and water(insolubles 1). The organic layer was separated from the filtrate, driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure. The residue was diluted with 100 ml of diethyl etherand 100 ml of ethyl acetate, and the insolubles were collected byfiltration (insolubles 2). Insolubles 1 described above was diluted with1000 ml of ethyl acetate, 500 ml of methanol, and 500 ml of acetone, andthe mixture was stirred for 45 minutes at room temperature. After theinsolubles were collected by filtration and the solvent was removedunder reduced pressure, the residue was diluted with 30 ml of diethylether and 15 ml of ethyl acetate, and the insolubles were collected byfiltration (insolubles 3). Insolubles 2 and insolubles 3 were combined,dissolved in 100 ml of acetone, diluted with 900 ml of ethyl acetate and400 ml of semi-saturated aqueous sodium hydrogen carbonate, and themixture was stirred at room temperature for 30 minutes. The insolubleswere removed by filtration, and the organic layer was separated from thefiltrate, washed three times with 500 ml of semi-saturatedaqueousesaline, dried over anhydrous magnesium sulfate, and evaporatedunder reduced pressure to give 5.71 g of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.31 (3H, d, J=7.4 Hz), 1.40 (3H, d, J=6.3 Hz), 3.37 (1H,dd, J₁=6.6 Hz, J₂=2.8 Hz), 3.47 (1H, m), 4.34 (1H, m), 4.38 (1H, dd,J₁=9.4 Hz, J₂=2.8 Hz), 5.28 (1H, d, J=13.7 Hz), 5.53 (1H, d, J=13.7 Hz),7.08 (1H, s), 7.68 (2H, d, J=8.5 Hz), 8.03 (1H, s), 8.24 (2H, d, J=8.5Hz), 8.34 (1H, s).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

To a solution of 4.70 g of 4-nitro-benzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 90 ml of THF and 50 ml of 1/15 M phosphate buffer (pH 6.8) was added7.0 g of 10% Pd-C. The reactor was purged with hydrogen, and thereaction mixture was stirred at room temperature for 4 hours. Thecatalyst was removed by filtration with Celite, and washed with 300 mlof water and 50 ml of THF. The filtrate was diluted with 200 ml of ethylacetate and washed with water. The aqueous layer was separated from thefiltrate, and concentrated under reduced pressure to a volume of about300 ml, which was purified by column chromatography on DIAION HP-20. Thefraction containing the aimed product was concentrated under reducedpressure, crystallized from 12 ml of water to give 656 mg of the titlecompound.

NMR (DMSO-d₆) δ: 1.18 (3H, d, J=6.1 Hz), 1.19 (3H, d, J=7.1 Hz), 3.32(1H, dd, J₁=6.3 Hz, J₂=2.8 Hz), 3.60 (1H, m), 4.00 (1H, m), 4.25 (1H,dd, J₁=9.6 Hz, J₂=2.8 Hz), 5.10 (1H, br), 7.02 (1H, s), 8.22 (1H, s),8.37 (1H, s). MS (TS): 334 (M⁺+H).

Example 2(1S,5R,6S)-6-((1R)-1-hydroxyethyl-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

A solution of 292 mg of 4-nitro-benzyl(1R,3R,5R,6S)-6-[(1R)-1-(t-butyldimethyl-silyloxy)ethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylatein 8 ml of dry acetonitrile was ice-cooled under the atmosphere ofargon, and 0.267 ml of N,N-diisopropylethylamine was added dropwise,followed by 0.103 ml of anhydrous trifluoromethanesulfonic acid. Afterthe reaction mixture was stirred at the same temperature for 30 minutes,it was diluted with ethyl acetate, a mixture of semi-saturated aqueoussaline saturated aqueous sodium hydrogen carbonate (pH 8.9), andsemi-saturated aqueous saline in this sequence. The organic layer wasdried over anhydrous magnesium sulfate, filtered, mixed with 3 ml ofN-methylpyrrolidinone, and the ethyl acetate was removed under reducedpressure. The residue was mixed with 17 mg oftris(dibenzylideneacetone)dipalladium (0), 17 mg oftri-2-furylphosphine, 376 mg of2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 1 ml of dryN-methylpyrrolidinone, and 167 mg of zinc chloride, and the mixture wasstirred under the atmosphere of argon at 50° C. for 4 hours. Thereaction mixture was diluted with ethyl acetate, and washed withsemi-saturated aqueous saline. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue thus obtained was purified by columnchromatography on silica gel (ethyl acetate) and on Sephadex LH-20(chloroform:methanol=1:1) in this sequence to give 111 mg of4-nitrobenzyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 0.08 (3H, s), 0.10 (3H, s), 0.86 (9H, s), 1.26 (3H, d,J=6.3 Hz), 1.28 (3H, d, J=7.7 Hz), 3.33 (1H, dd, J₁=4.7 Hz, J₂=2.8 Hz),3.41 (1H, m), 4.31 (1H, m), 4.37 (1H, dd, J₁=9.6 Hz, J₂=2.8 Hz), 5.26(1H, d, J=13.7 Hz), 5.49 (1H, d, J=13.7 Hz), 7.26 (1H, s), 7.67 (2H, d,J=8.3 Hz), 8.03 (1H, s), 8.23 (2H, d, J=8.3 Hz), 8.33 (1H, s).

b) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 111 mg of 4-nitrobenzyl(1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 3 ml of anhydrous THF were added 0.164 ml of acetic acid and 0.954 mlof a 1 M solution of tetra-n-butylammonium fluoride/THF, and the mixturewas stirred at room temperature under the atmosphere of argon at 20hours. The reaction mixture was diluted with ethyl acetate, and washedwith a mixed solvent of semi-saturated aqueous saline and saturatedaqueous sodium hydrogen carbonate (pH 8.0), and semi-saturated aqueoussaline in this sequence. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and the solvent was removed bydistillation. The residue thus obtained was purified by columnchromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 57.3mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

The NMR data was well agreed with those in Example 1-a).

c)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 1-b),(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid was obtained from 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

The NMR data was well agreed with those in Example 1-a).

Example 3 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a suspension of 947 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid in 180 ml of water was added 7.8 ml of 0.1 N aqueous sodiumhydrogen carbonate, and the mixture was stirred at room temperature for2 hours to form a solution, which was then frozen. The frozen solutionwas dissolved in 12 ml of dry DMF, mixed with 0.36 ml of iodomethylpivalate under the atmosphere of argon at −30° C., and stirred for 1.5hours during which the temperature was raised up to −10° C. The reactionmixture was diluted with 100 ml of ethyl acetate, and washed with 100 mlof semi-saturated aqueous saline. The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to a total volume of 5 ml. The residue thus obtained waspurified by column chromatography on silica gel (chloroform:methanol10:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequenceto give 576 mg of the title compound.

NMR (CDCl₃) δ: 1.20 (9H, s), 1.29 (3H, d, J=7.2 Hz), 1.36 (3H, d, J=6.2Hz), 3.33 (1H, dd, J₁=6.5 Hz, J₂=2.8 Hz), 3.45 (1H, m), 4.29 (1H, m),4.35 (1H, dd, J₁=9.7 Hz, J₂=2.8 Hz), 5.88 (1H, d, J=5.6 Hz), 5.98 (1H,d, J=5.6 Hz), 7.07 (1H, s), 8.06 (1H, s), 8.34 (1H, s). MS(TS):448(M⁺+H).

Example 4(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateIodide

To a solution of 64.7 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 1 ml of dry dichloromethane was added 0.86 ml of iodomethane, and themixture was stirred under the atmosphere of argon in darkness at roomtemperature for 21 hours. Evaporation of the unreacted reagent underreduced pressure gave 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18 (3H, d, J=6.6 Hz), 1.22 (3H, d, J=7.4 Hz), 3.49(1H, dd), 3.73 (1H, m), 4.05 (1H, m), 4.07 (3H, s), 4.39 (1H, dd), 5.18(1H, d), 5.39 (1H, d, J=14.3 Hz), 5.51 (1H, d, J=14.3 Hz), 7.72 (2H, d,J=8.8 Hz), 7.80 (1H, s), 8.22 (2H, d, J=8.8 Hz), 8.61 (1H, s), 9.51 (1H,s).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

The total volume of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateiodide was dissolved in a mixture of 2 ml of THF and 2 ml of {fraction(1/15)} M phosphate buffer (pH 6.8), 77 mg of 10% Pd-C was added. Thereactor was purged with hydrogen, and the reaction mixture was stirredat room temperature for 5 hours. The catalyst was collected byfiltration with Celite and washed with water. The filtrate was washedwith 20 ml of ethyl acetate, and purified by column chromatography onDIAION HP-20 to give 14.1 mg of the title compound.

NMR (D₂O) δ(HOD=4.80 ppm): 1.23 (3H, d, J=7.1 Hz), 1.30 (3H, d, J=6.3Hz), 3.53 (1H, dd, J₁=6.1 Hz, J₂=2.5 Hz), 4.06 (3H, s), 4.28 (2H, m),7.47 (1H, s), 8.05 (1H, s), 9.10 (1H, s).

Example 5(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 491 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylatein 12 ml of dry acetonitrile was added dropwise 0.59 ml ofN,N-diisopropylethylamine followed by 0.227 ml of anhydroustrifluoromethanesulfonic acid under the atmosphere of argon at −15° C.After the reaction mixture was stirred at the same temperature for 30minutes, it was diluted with 40 ml of ethyl acetate and washedsequentially with semi-saturated aqueous saline, a mixed solvent ofsemi-saturated aqueous saline and 1N aqueous hydrochloric acid (pH 1.1),a mixed solvent of semi-saturated aqueous saline and saturated aqueoussodium hydrogen carbonate(pH 8.9), and semi-saturated aqueous saline.The organic layer was dried over anhydrous magnesium sulfate, filtered,and the solvent was removed under reduced pressure. The residue thusobtained was dissolved in 4 ml of dry N-methylpyrrolidinone, mixed with37 mg of tri-2-furylphosphine, 370 mg of zinc chloride, 37 mg oftris(dibenzylideneacetone)dipalladium (0), and a solution of 765 mg of3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 2 ml of dryN-methylpyrrolidinone, and the mixture was stirred under the atmosphereof argon at 50° C. for 40 minutes. The reaction mixture was diluted with200 ml of ethyl acetate and 200 ml of water, and the organic layer wasseparated. The organic layer was diluted with 100 ml semi-saturatedaqueous sodium hydrogen carbonate and stirred for 30 minutes to removeinsolubles by filtration. The organic layer of the filtrate wasseparated, washed three times with 200 ml of semi-saturated aqueoussaline, dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue thus obtained was purifiedby column chromatography on silica gel (chloroform:methanol=30:1) togive 225 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.16 (3H, d, J=7.2 Hz), 1.36 (3H, d, J=6.3 Hz), 3.48 (1H,dd, J₁=5.9 Hz, =3.2 Hz), 3.65 (1H, m), 4.34 (1H, m), 4.55 (1H, dd,J₁=10.4 Hz, J₂=3.2 Hz), 5.12 (1H, d, J=13.4 Hz), 5.30 (1H, d, J=13.4Hz), 6.98 (1H, s), 7.06 (1H, s), 7.35 (2H, d, J=8.9 Hz), 7.89 (1H, s),8.12 (2H, d, J=8.9 Hz).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

To a solution of 4.70 g of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 10 ml of THF and 10 ml of {fraction (1/15)} M phosphate buffer wasadded 240 mg of 10% Pd-C. The reactor was purged with hydrogen, and thereaction mixture was stirred at room temperature for 3 hours. Thecatalyst was collected by filtration and washed with water. The filtratewas washed with ethyl acetate, and the aqueous layer was purified bycolumn chromatography on DIAION HP-20 to give 27.5 mg of the titlecompound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.16 (3H, d, J=7.1 Hz), 1.32 (3H, d, J=6.3Hz), 3.50-3.65 (2H, m), 4.25-4.48 (2H, m), 7.42 (1H, s), 7.45 (1H, s),8.70 (1H, s).

Example 6 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a suspension of 32.5 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid in a mixture of 10 ml of water and 8 ml of methanol was added 7.8mg of sodium hydrogen carbonate, and the mixture was stirred at roomtemperature for 10 minutes to form a solution. Methanol was removedunder reduced pressure, and the residue was lyophilized. The lyophilizedproduct was dissolved in 2 ml of dry DMF, 0.03 ml of iodomethyl pivalatewas added under the atmosphere of argon at −30° C., and the mixture wasstirred for 2 hours during which the temperature was raised up to −10°C. Ethyl acetate was added to the reaction mixture, and the mixture waswashed with semi-saturated aqueous saline. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to a total volume of 3 ml. The residue thus obtainedwas purified by column chromatography on silica gel(chloroform:methanol=30:1-10:1) to give 26.6 mg of the title compound.

NMR (CDCl₃) δ: 1.14 (3H, d, J=7.4 Hz), 1.17 (9H, s), 1.37 (3H, d, J=6.3Hz), 3.43 (1H, dd, J₁=6.3 Hz, J₂=3.1 Hz), 3.70 (1H, m), 4.32 (1H, m),4.48 (1H, dd, J₁=10.4 Hz, J₂=3.1 Hz), 5.74 (1H, d, J=5.5 Hz), 5.87 (1H,d, J=5.5 Hz), 7.07 (1H, s), 7.13 (1H, s), 7.85 (1H, s).

Example 7(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate(innersalt)

a) 4-Nitrobenxyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylateIodide

To a suspension of 102 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate1.5 ml of dry dichloromethane was added 2.7 ml of iodomethane, and themixture was stirred under the atmosphere of argon in the darkness atroom temperature for 3 days. Unreacted reagent was removed under reducedpressure to give 122 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylateiodide.

NMR (DMSO-d₆) δ: 1.06 (3H, d, J=7.6 Hz), 1.17 (3H, d, J=6.3 Hz), 3.55(1H, dd, J₁=5.5 Hz, J₂=3.2 Hz), 3.66 (1H, m), 3.94 (1H, m), 3.98 (3H,s), 4.44 (1H, dd, J₁=10.5 Hz, J₂=3.2 Hz), 5.19 (1H, d, J=13.4 Hz), 5.28(1H, d, J=13.4 Hz), 7.49 (2H, d, J=8.8 Hz), 7.72 (1H, s), 7.82 (1H, s),8.19 (2H, d, J=8.8 Hz), 9.73 (1H, s).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

To a solution of 60.5 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylatein 1.8 ml of THF and 1.8 ml of {fraction (1/15)} M phosphate buffer (pH6.8) was added 71 mg of 10% Pd-C. The reactor was purged with hydrogen,and the reaction mixture was stirred at room temperature for 3.5 hours.The catalyst was collected by filtration through Celite, and washed withwater. The filtrate was washed with 20 ml of ethyl acetate, and purifiedby column chromatography on DIAION HP-20 and on COSMOSEAL40C18-PREP(water:methanol=20:1) to give 8.3 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.14 (3H, d, J=7.4 Hz), 1.31 (3H, d, J=6.3Hz), 3.55 (1H, m), 3.62 (1H, dd, J₁=5.8 Hz, J₂=2.9 Hz), 4.06 (3H, s),4.30 (1H, m), 4.43 (1H, dd, J₁=9.9 Hz, J₂=2.9 Hz), 7.52 (1H, s), 7.61(1H, s), 9.06 (1H, s).

Example 8(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-Nitrobenzoyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

To ice-cooled solution of 149 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate in 4ml of dry acetonitrile was added dropwise 0.187 ml ofN,N-diisopropylethylamine, followed by 0.071 ml of anhydroustrifluoro-methanesulfonic acid under the atmosphere of argon. Thesolution was stirred at the same temperature for 30 minutes, dilutedwith ethyl acetate, and washed sequentially with a mixed solvent ofsemi-saturated aqueous saline and saturated aqueous sodium hydrogencarbonate (pH 8.9), and semi-saturated aqueous saline. The organic layerwas dried over anhydrous magnesium sulfate, filtered, and the solventwas removed under reduced pressure. The residue thus obtained wasdissolved in 2 ml of dry N-methylpyrrolidinone, added with 12 mg oftri-2-furylphosphine, 116 mg of zinc chloride, 12 mg oftris(dibenzylideneacetone)dipalladium (0), and a solution of 306 mg of2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 1 ml of dryN-methylpyrrolidinone, and the mixture was stirred under the atmosphereof argon at 50° C. for 2 hours. The reaction mixture was diluted with 50ml of ethyl acetate and 50 ml water, and insolubles were removed byfiltration, and washed with ethyl acetate. The organic layer of thefiltrate was separated, dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on Sephadex LH-20(chloroform:methanol=1:1). The fraction containing the aimed product wasconcentrated under reduced pressure, and triturated with 13 ml ofdiethyl ether to collect insolubles and thus to give 38.5 mg of4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.17 (3H, d, J=6.2 Hz), 3.31 (1H, m), 3.40-3.55 (3H,m), 4.01 (1H, m), 4.24 (1H, m), 5.15 (1H, d, J=4.9 Hz), 5.41 (1H, d,J=14.0 Hz), 5.53 (1H, d, J=14.0 Hz), 7.04 (1H, s), 7.75 (2H, d, J=8.9Hz), 8.24 (2H, d, J=8.9 Hz), 8.28 (1H, s), 8.37 (1H, s).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

To a solution of 41 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatein 2 ml of THF and 2 ml of {fraction (1/15)} M phosphate buffer (pH 6.8)was added 61 mg of 10% Pd-C. The reactor was purged with hydrogen, andthe reaction mixture was stirred at room temperature for 2 hours. Thecatalyst was removed by filtration on Celite and washed with water. Thefiltrate was washed with ethyl acetate, and the aqueous layer waspurified by column chromatography on DIAION HP-20 to give 5.7 mg of thetitle compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31 (3H, d, J=6.3 Hz), 3.30 (2H, m), 3.53(1H, dd, J₁=5.9 Hz, J₂=3.0 Hz), 4.26 (2H, m), 7.37 (1H, s), 7.89 (1H,s), 8.88 (1H, s).

Example 9(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

To a solution of 353.2 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylatein 7 ml of dry acetonitrile was added dropwise 0.34 ml ofN,N-diisopropylethylamine, followed by 0.18 ml of anhydroustrifluoromethanesulfonic acid under the atmosphere of argon at −15° C.After the reaction mixture was stirred at the same temperature 30minutes, it was diluted with 10 ml of ethyl acetate, washed sequentiallywith semi-saturated aqueous saline, a mixed solution of semi-saturatedaqueous saline and 1 N hydrochloric acid, a mixed solution ofsemi-saturated aqueous saline and saturated aqueous sodium hydrogencarbonate, and semi-saturated aqueous saline. The organic layer wasdried over anhydrous magnesium sulfate, filtered, mixed with 2 ml of dryN-methylpyrrolidinone, and ethyl acetate was removed under reducedpressure. To the residue were added a solution of 26.8 mg oftris(dibenzylideneacetone)dipalladium(0), 27.2 mg oftri-2-furylphosphine and 470 mg of3-methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole in 0.5 ml of dryN-methylpyrrolidinone 0.5 ml, and 266 mg of zinc chloride, and themixture was stirred under the atmosphere of argon at 50° C. for 1 hour.The solvent was concentrated under reduced pressure, diluted with 20 mlof ethyl acetate and 80 ml of water, and adjusted weak alkaline withsaturated aqueous sodium hydrogen carbonate. The insolubles werecollected by filtration, the residue was dissolved in acetone, and thesolubles were concentrated. Further, the organic layer of the filtratewas separated, washed once with 20 ml of saturated aqueous saline,combined with the acetone solubles, dried over anhydrous magnesiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel (ethylacetate:methanol=95:5) to give 5.71 g of 4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.11 (3H, d, J=7.3 Hz), 1.30 (3H, d, J=6.3 Hz), 2.14 (3H,s), 3.31-3.41 (2H, m), 4.26 (1H, m), 4.39 (1H, dd, J₁=0.2 Hz, J₂=3.6Hz), 5.13 (1H, d, J=13.7 Hz), 5.33 (1H, d, J=13.7 Hz), 7.02 (1H, s),7.43 (2H, d, J=8.5 Hz), 7.80 (1H, s), 8.05 (2H, d, J=8.5 Hz). MS (FAB⁺):483 (M⁺+H).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

To a solution of 157.3 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatein 3 ml of THF and 3 ml of {fraction (1/15)} M phosphate buffer (pH 6.8)was added 0.24 g of 100 Pd-C. The reactor was purged with hydrogen, thereaction mixture was stirred at room temperature for 1 hour. Thecatalyst was collected by filtration, and washed with 50 ml of water.The filtrate was diluted with 20 ml of ethyl acetate, separated, and theorganic layer was further washed with water. The combined aqueous layerwas concentrated under reduced pressure to a volume of about 30 ml. Theresidual concentrate was purified by column chromatography on DIAIONHP-20. The fraction containing the aimed product was lyophilized to give63.5 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.16 (3H, d, J=7.1 Hz), 1.30 (3H, d, J=6.3Hz), 2.38 (3H, s), 3.40(1H, m), 3.57 (1H, m), 4.28 (1H, m), 4.38 (1H,dd, J₁=9.7 Hz, J₂=3.0 Hz), 7.50 (1H, s), 9.00 (1H, s). MS(FAB⁺)-:348(M⁺+H).

Example 10 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

To a solution of 29.4 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatein 0.8 ml of dry DMF was added 0.017 ml of iodomethyl pivalate under theatmosphere of argon at −30° C., and the mixture was stirred for 4 hoursduring which the temperature was raised up to 10° C. The reactionmixture was diluted with 10 ml of ethyl acetate, separated, and theaqueous layer was extracted twice with ethyl acetate, while the organiclayer was washed with 10 ml of semi-saturated aqueous saline. Thecombined organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to a volume of 1 ml.The residue thus obtained was purified by column chromatography onsilica gel (chloroform:methanol=20:1) and on Sephadex LH-20(dichloromethane:methanol=1:1) in this sequence to give 7.9 mg of thetitle compound.

NMR (CDCl₃) δ: 1.02(9H, S), 1.09(3H, d, J=7.4 Hz), 1.29(3H, d, J=6.3Hz), 3.27-3.34(2H, m), 4.24(1H, m), 4.33(1H, dd, J₁=9.7 Hz, J₂=2.8 Hz),5.69(1H, d, J=5.5 Hz), 5.82(1H, d, J=5.5 Hz), 7.02(1H, s), 7.88(1H, s).

Example 11(1S,5R,6S)-2-(3,6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

To a solution of 73.6 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatein 0.5 ml of dry dichloromethane was added 0.95 ml of iodomethane, andthe mixture was stirred under the atmosphere of argon in the darkness atroom temperature for 18 hours. Unreacted reagent was removed underreduced pressure to give 89.1 mg of 4-nitrobenzyl(1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide.

NMR (CD₃OD) δ: 0.99(3H, d, J=7.4 Hz), 1.09(3H, d, J=6.0 Hz), 2.10(3H,s), 3.10(1H, m), 3.92(3H, s), 3.98(1H, m), 4.29(1H, dd, J₁=10.5 Hz,J₂=3.0 Hz), 5.02(1H, d, J=13.1 Hz), 5.15(1H, d, J=13.1 Hz), 7.34(2H, d,J=8.5 Hz), 7.54(1H, s), 7.89(2H, d, J=8.5 Hz), 9.26(1H, s).

b)(1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

To a solution of 89.1 mg of 4-nitrobenzyl(1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide in 2 ml of THF and 2 ml of {fraction (1/15)} M phosphate buffer(pH 6.8) was added 102.7 mg of 10% Pd-C. The reactor was purged withhydrogen, the reaction mixture was stirred at room temperature for 5hours. The catalyst was collected by filtration, and washed with water.The filtrate was diluted with 20 ml of ethyl acetate 20 ml, separated,and the organic layer was further washed with water. The combinedaqueous layer was concentrated under reduced pressure to a volume ofabout 30 ml. The concentrate was purified by column chromatography onDIAION HP-20 to give 17.0 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.16(3H, d, J=7.2 Hz), 1.30(3H, d, J=6.3Hz), 2.37(3H, s), 3.40(1H, m), 3.58(1H, m), 4.09(3H, s), 4.28(1H, m),4.39(1H, dd, J₁=9.8 Hz, J₂=2.2 Hz), 7.58(1H, s), 9.22(1H, s).

Example 12(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

To an ice-cooled solution of 493 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate in13 ml of dry acetonitrile 13 ml was added dropwise 0.619 ml ofN,N-diisopropylethylamine, followed by 0.235 ml of anhydroustrifluoro-methanesulfonic acid under the atmosphere of argon. After thereaction mixture was stirred at the same temperature for 30 minutes, itwas diluted with ethyl acetate, and washed with semi-saturated aqueoussaline, a mixed solution of semi-saturated aqueous saline and 1 Nhydrochloric acid (pH 1.1), a mixed solution of semi-saturated aqueoussaline and saturated aqueous sodium hydrogen carbonate (pH 8.9), andsemi-saturated aqueous saline in this sequence.-The organic layer wasdried over anhydrous magnesium sulfate, filtered, and the solvent wasremoved under reduced pressure. The residue thus obtained was dissolvedin 5 ml of dry N-methylpyrrolidinone, mixed with 40 mg oftri-2-furylphosphine, 384 mg of zinc chloride, 40 mg oftris(dibenzylideneacetone)dipalladium (0), and 950 mg of3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 2 ml of dryN-methyl-pyrrolidinone, and the mixture was stirred under the atmosphereof argon at 50° C. for 1.5 hours. The reaction mixture was diluted with50 ml of ethyl acetate and 50 ml of semi-saturated aqueous sodiumhydrogen carbonate, the insolubles was removed by filtration, and thefiltrate was washed with ethyl acetate. The organic layer of thefiltrate was separated, dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on silica gel(chloroform:methanol=15:1) to give 303 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.40(3H, d, J=6.3 Hz), 3.38(3H, m), 4.33(1H, m), 4.44(1H,m), 5.22(1H, d, J=13.2 Hz), 5.36(1H, d, J=13.2 Hz), 7.06(1H, s),7.09(1H, s), 7.43(2H, d, J=8.9 Hz), 7.75(1H, s), 8.18(2H, d, J=8.9 Hz).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

To a solution of 203 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatein 4 ml of THF and 4 ml of 1/15 M phosphate buffer (pH 6.8) was added152 mg of 10% Pd-C. The reactor was purged with hydrogen, the reactionmixture was stirred at room temperature for 1 hour. The catalyst wascollected by filtration on Celite, and washed with water. The filtratewas washed with ethyl acetate, and then the aqueous layer was purifiedby column chromatography on DIAION HP-20, followed by crystallizationform 1 ml of water to give 32.8 mg of the title compound.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=6.3 Hz), 3.20(1H, m), 3.55(2H, m),3.99(1H, m), 4.28(1H, m), 5.14(1H, m), 7.06(1H, s), 7.34(1H, s),7.99(1H, s).

Example 13 pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

To a suspension of 42.1 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid 10 ml of water was added 1.3 ml of a 0.1 N aqueous sodium hydrogencarbonate solution, and the mixture was stirred at room temperature for1 hour to form a solution, which was then lyophilized. The lyophilizedproduct was dissolved in 1 ml of dry DMF, 0.034 ml of iodomethylpivalate was added under the atmosphere of argon at −30° C., and themixture was stirred for 1.5 hours during which the temperature wasraised up to −10° C. The reaction mixture was diluted with 20 ml ofethyl acetate, and washed with semi-saturated aqueous saline. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to a volume of 3 ml, The residuethus obtained was purified by column chromatography on silica gel(chloroform:methanol=15:1) and on Sephadex LH-20(chloroform:methanol=1:1) in this sequence to give 27.2 mg of the titlecompound.

NMR (CDCl₃) δ: 1.19(9H, s), 1.38(3H, d, J=6.2 Hz), 3.37(3H, m), 4.29(1H,m), 4.42(1H, m), 5.78(1H, d, J=5.5 Hz), 5.88(1H, d, J=5.5 Hz), 7.13(2H,s), 7.80(1H, s).

Example 14(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

To a suspension of 100 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatein 1.5 ml of dry dichloromethane was added 1.37 ml of iodomethane, andthe mixture was stirred under the atmosphere of argon in the darkness atroom temperature for 24 hours. Unreacted reagent was removed underreduced pressure. The residue thus obtained was dissolved in 4 ml of THFand 4 ml of 1/15 M phosphate buffer (pH 6.8), and 160 mg of 10% Pd-C wasadded. The reactor was purged with hydrogen, the reaction mixture wasstirred at room temperature for 3.5 hours. The catalyst was collected byfiltration on Celite and washed with water. The filtrate was washed withethyl acetate, and purified by column chromatography on DIAION HP-20 andCOSMOSEAL 40C18-PREP (water:methanol=20:1) to give 4.8 mg of the titlecompound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(3H, d, J=6.5 Hz), 3.25(1H, m), 3.45(1H,m), 3.60(1H, dd, J₁=6.0 Hz, J₂=3.2 Hz), 4.08(3H, s), 4.28(1H, m),4.39(1H, m), 7.49(1H, s), 7.62(1H, s), 8.93(1H, s).

Example 15(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateIodide

To 51.6 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas added 1.5 ml of iodomethane, and the mixture was stirred under theatmosphere of argon in the darkness at room temperature for 2 days.Unreacted reagent was removed under reduced pressure to give 59.5 mg of4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.2 Hz), 3.45(2H, m), 3.58(1H, dd, J₁=5.8Hz, J₂=3.1 Hz), 4.05(1H, m), 4.07(3H, s), 4.31(1H, m), 5.44(1H, d,J=13.5 Hz), 5.55(1H, d, J=13.5 Hz), 7.75(2H, d, J=8.8 Hz), 7.81(1H, s),8.25(2H, d, J=8.8 Hz), 8.59(1H, s), 9.53(1H, s).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

To a solution of 58 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateiodide in 2 ml of THF and 2 ml of 1/15 M phosphate buffer (pH 6.8) wasadded 68 mg of 10% Pd-C. The reactor was purged with hydrogen, and thereaction mixture was stirred at room temperature for 4 hours. Thecatalyst was collected by filtration on Celite, and washed with water.The filtrate was washed with ethyl acetate, the aqueous layer waspurified by column chromatography on DIAION HP-20 to give 5.4 mg of thetitle compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.29(3H, d, J=6.5 Hz), 3.31(2H, m), 3.53(1H,dd, J₁=5.8 Hz, J₂=3.0 Hz), 4.05(3H, s), 4.25(2H, m), 7.47(1H, s),7.90(1H, s), 9.09(1H, s).

Example 16 (1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 88-a) described below, 4-nitrobenzyl(1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was obtained from 64.3 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.3 Hz), 1.22(3H, d, J=7.2 Hz), 3.50(1H,dd, J₁=5.7 Hz, J₂=3.0 Hz), 3.72(1H, m), 4.05(1H, m), 4.38(1H, m),5.18(2H, s), 5.40(1H, d, J=13.8 Hz), 5.51(1H, d, J=13.8 Hz), 7.59(1H,s), 7.71(2H, d, J=9.0 Hz), 7.83(2H, m), 8.22(2H, d, J=9.0 Hz), 8.64(1H,s), 9.54(1H, s).

b)(1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), 58.6 mg of the title compound wasobtained from the total amount of 4-nitrobenzyl(1S,5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide obtained above.

NMR (D₂O) δ (HOD=4.80 ppm): 1.26(3H, d, J=7.2 Hz), 1.31(3H, d, J=6.4Hz), 3.57(1H, dd, J₁=6.1 Hz, J₂=2.8 Hz), 3.66(1H, m), 4.28(1H, m),4.36(1H, dd, J₁=9.3 Hz, J₂=2.8 Hz), 5.25(2H, s), 7.57(1H, s), 8.13(1H,s), 9.25(1H, s).

Example 17(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 433 mg of 4-nitro-benzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 724 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.04 g of 5-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.4 Hz), 1.39(3H, d, J=6.3 Hz), 2.59(3H,s), 3.36(1H, dd, J₁=6.5 Hz, J₂=2.8 Hz), 3.46(1H, m), 4.32(1H, m),4.37(1H, dd, J₁=9.6 Hz, J₂=2.8 Hz), 5.27(1H, d, J=13.8 Hz), 5.53(1H, d,J=13.8 Hz), 6.92(1H, s), 7.67(2H, d, J=8.7 Hz), 8.19(1H, s), 8.22(2H, d,J=8.5 Hz).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as Example 5-b), 98.5 mg of the title compound wasobtained from 326 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.21(3H, d, J=7.1 Hz), 1.29(3H, d, J=6.4Hz), 2.77(3H, s), 3.51(1H, dd, J₁=6.0 Hz, J₂=2.7 Hz), 3.60(1H, m),4.27(2H, m), 7.25(1H, s), 7.92(1H, s).

Example 18(1S,5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-²-em-3-carboxylate(inner salt)

In the same manner as in Example 14 except that purification was carriedout by column chromatography on DIAION HP-20, 19.1 mg of the titlecompound was obtained from 107 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.26(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.4Hz), 2.78(3H, s), 3.55(1H, dd, J₁=6.1 Hz, J₂=2.8 Hz), 3.64(1H, m),3.92(3H, s), 4.28(1H, m), 4.33(1H, dd, J₁=9.3 Hz, J₂=2.8 Hz), 7.37(1H,s), 7.97(1H, s).

Example 19 pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

To a solution of 46.8 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid 5 ml of water was added 134 ml of a 0.1 N aqueous sodium hydrogencarbonate solution. The mixture was lyophilized, dissolved in 1 ml ofDMF, added with 0.034 ml of pivaloyloxymethyl iodide under theatmosphere of argon at −30° C., and stirred at the same temperature for1.5 hours. The reaction mixture was diluted with 50 ml of ethyl acetate,and washed with 50 ml of semi-saturated aqueous saline. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to a volume of 1 ml. The residuethus obtained was purified by column chromatography on silica gel(dichloromethane:methanol=20:1) and on SephadexLH-20(chloroform:methanol=1:1) in this sequence to give 44.5 mg of thetitle compound.

NMR (CDCl₃) δ: 1.21(9H, s), 1.28(3H, d, J=7.1 Hz), 1.37(3H, d, J=6.3Hz), 2.63(3H, s), 3.32(1H, dd, J₁=6.7 Hz, J₂=2.8 Hz), 3.44(1H, m),4.31(2H, m), 5.87(1H, d, J=5.6 Hz), 5.99(1H, d, J=5.6 Hz), 6.92(1H, s),8.16(1H, s).

Example 20(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 183 mg of4-nitrobenzyl(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 724 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.07 g of 7-chloro-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.31(3H, d, J=7.4 Hz), 1.40(3H, d, J=6.3 Hz), 3.37(1H,dd, J₁=6.5 Hz, J₂=2.7 Hz), 3.46(1H, m), 4.35(2H, m), 5.28(1H, d, J=13.5Hz), 5.52(1H, d, J=13.5 Hz), 7.68(2H, d, J=8.9 Hz), 7.89(1H, s),8.24(2H, d, J=8.9 Hz)), 8.27(1H, s).

b)(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 8.2 mg of the title compound wasobtained from 134 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=7.1 Hz), 1.32(3H, d, J=6.3Hz), 3.53(2H, m), 4.29(2H, m), 7.81(1H, s), 7.98(1H, s).

Example 21(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 40.4 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatefrom 190 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 272 mg of 2-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.00(3H, m), 1.17(3H, d, J=6.1 Hz), 2.14(3H, s),3.56(1H, m), 3.78(1H, m), 4.06(1H, m), 4.55(1H, m), 5.10-5.40(3H, m),7.00(1H, m), 7.50-7.70(2H, m), 8.12-8.28(3H, m).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 11.9 mg of the title compound wasobtained from 40.4 mgo of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.06(3H, d, J=7.1 Hz), 1.32(3H, d, J=6.4Hz), 2.42(3H, s), 3.62(2H, m), 4.31(1H, m), 4.46(1H, dd, J₁=9.9 Hz,J₂=2.8 Hz), 7.52(1H, s), 8.98(1H, s).

Example 22(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 123 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 270 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and406 mg of 2-methyl-3-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.37(3H, d, J=6.2 Hz), 2.18(3H, s), 3.27(2H, br.s),3.44(1H, dd, J₁=5.7 Hz, J₂=2.5 Hz), 4.31(1H, m), 4.51(1H, m), 5.15(1H,d, J=13.4 Hz), 5.30(1H, d, J=13.4 Hz), 6.99(1H, s), 7.33(2H, d, J=8.7Hz), 7.78(1H, s), 8.11(2H, d, J=8.7 Hz).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 12.9 mg of the title compound wasobtained from 73 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(2-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.4 Hz), 2.36(3H, s), 3.14(1H,dd, J₁=17.7 Hz, J₂=10.1 Hz), 3.38(1H, dd, J₁=17.7 Hz, J₂=8.6 Hz),3.61(1H, dd, J₁=5.9 Hz, J₂=2.9 Hz), 4.28(1H, m), 4.42(1H, m), 7.47(1H,s), 8.80(1H, s).

Example 23(1S,5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a) except that the reaction wascarried out for 4 days, 4-nitrobenzyl(1S,5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was obtained from 49 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.2 Hz), 1.22(3H, d, J=7.4 Hz), 3.50(1H,dd, J₁=5.9 Hz, J₂=2.8 Hz), 3.25(1H, m), 4.01(3H, s), 4.03(1H, m),4.40(1H, dd, J₁=10.3 Hz, J₂=2.8 Hz), 5.41(1H, d, J=13.9 Hz), 5.53(1H, d,J=13.9 Hz), 7.74(2H, d, J=8.9 Hz), 8.24(2H, d, J=8.9 Hz), 8.71(1H, s),9.69(1H, s).

b)(1S,5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), 12.1 mg of the title compound wasobtained from the whole amount of 4-nitrobenzyl(1S,5R,6S)-2-(7-chloro-6-methylimiazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide obtained above.

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.4Hz), 3.54(1H, dd, J₁=6.1 Hz, J₂=2.9 Hz), 3.63(1H, m), 4.01(3H, s),4.27(1H, m), 4.32(1H, dd, J₁=9.4 Hz, J₂=2.9 Hz), 8.11(1H, s), 9.26(1H,s).

Example 24 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 14.6 mg of the title compound wasobtained from 30.6 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.23(9H, s), 1.37(3H, d, J=6.2 Hz), 3.30(3H, m), 4.30(2H,m), 5.91(1H, d, J=5.5 Hz), 6.01(1H, d, J=5.5 Hz), 7.07(1H, s), 8.05(1H,s), 8.31(1H, s).

Example 25(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 218 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 730 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and730 mg of 5-methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.40(3H, d, J=6.4 Hz), 2.59(3H, s), 3.32(3H, m), 4.32(2H,m), 5.31(1H, d, J=13.8 Hz), 5.56(1H, d, J=13.8 Hz), 6.91(1H, s),7.70(2H, d, J=8.9 Hz), 8.11(1H, s), 8.25(2H, d, J=8.9 Hz).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 46.5 mg of the title compound wasobtained from 161 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.4 Hz), 2.72(3H, s), 3.23(2H,m), 3.50(1H, dd, J₁=5.8 Hz, J₂=3.0 Hz), 4.24(2H, m), 7.23(1H, s),7.72(1H, s).

Example 26 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 20.0 mg of the title compound wasobtained from 40.2 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.23(9H, s), 1.36(3H, d, J=6.2 Hz), 2.61(3H, s), 3.26(1H,dd, J₁=6.6 Hz, J₂=2.8 Hz), 3.33(2H, m), 4.30(2H, m), 5.90(1H, d, J=5.5Hz), 6.01(1H, d, J=5.5 Hz), 6.91(1H, s), 8.12(1H, s).

Example 27 Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 110 mg of 4-nitro-benzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas prepared as a yellow solid from 725 mg 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapen-2-em-3-carboxyateand 1.04 g of 7-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.2 Hz), 1.40(3H, d, J=6.2 Hz), 2.34(3H,s), 3.34-3.49(2H, m), 4.28-4.39(2H, m), 5.27(1H, d, J=13.7 Hz), 5.52(1H,d, J=13.7 Hz), 7.67(2H, d, J=6.9 Hz), 7.95(1H, s), 8.23(2H, d, J=6.9Hz), 8.24(1H, s). MS (TSP): 483 (M⁺+H).

b) Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

1.5 mg of the title compound was obtained in the same manner as inExample 134-d) described below except that the reaction was carried outwith 90 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate,and purification was carried out with CHP-20P (3% THF in water).

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.3Hz), 2.34(3H, s), 3.48-3.59(2H, m), 4.21-4.32(2H, m), 7.78(1H, s),8.01(1H, s). MS(FAB⁺): 392 (M⁺+Na), 370 (M⁺+H).

Example 28 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135 described below, 28 mg of the titlecompound was obtained from 42.8 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.21(9H, s), 1.29(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.2Hz), 2.34(3H, s), 3.32(1H, dd, J₁=7.0 Hz, J₂=2.9 Hz), 3.40-3.48(1H, m),4.25-4.35(2H, m), 5.88(1H, d, J=5.6 Hz), 5.99(1H, d, J=5.6 Hz), 7.96(1H,s), 8.25(1H, s). MS (TSP): 462 (M⁺+H).

Example 29(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 18.8 mg of 4-nitrobenzyl(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was obtained as a yellowish orange oil by using 18.5 mg of4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylateand 0.5 ml of methyl iodide.

NMR (Acetone-d₆) δ: 1.31(3H, d, J=6.3 Hz), 1.36(3H, d, J=7.2 Hz),2.63(3H, s), 3.55(1H, dd, J₁=6.3 Hz, J₂=3.0 Hz), 3.82-3.92(1H, m),4.22(3H, s), 4.35-4.45(1H, br.s), 4.55(1H, dd, J₁=9.9 Hz, J₂=3.0 Hz),5.44(1H, d, J=13.8 Hz), 5.62(1H, d, J=13.8 Hz), 7.83(2H, d, J=6.9 Hz),8, 25(2H, d, J=6.9 Hz), 9.01(1H, s), 9.85(1H, s). MS (TSI): 497 (M⁺).

b)(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b) except that 18.8 mg of4-nitrobenzyl(1S,5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was used and purification was carried out on CHP-20P (2% THF inwater), 9.3 mg of the title compound was obtained as a yellow amorphousproduct.

NMR (D₂O) δ (HOD=4.80 ppm): 1.25(3H, d, J=7.1 Hz), 1.31(3H, d, 6.3 Hz),2.41(3H, s), 3.53-3.65(2H, m), 3.93(3H, s), 4.22-4.36(2H, m), 8.01(1H,s), 9.05(0.5H, s, partially exchanged with D₂O). MS (FAB⁺): 362 (M⁺+H).

Example 30(5R,6S-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em3-carboxylateIodide

In the same manner as in Example 4-a) except that the reaction wascarried out for 3 days, 4-nitrobenzyl(5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide was obtained from 57 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=6.2 Hz), 2.82(3H, s), 3.48(2H, m),3.59(1H, dd, J₁=5.5 Hz, J₂=3.1 Hz), 3.92(3H, s), 4.04(1H, m), 4.33(1H,m), 5.44(1H, d, J=13.7 Hz), 5.55(1H, d, J=13.7 Hz), 7.71(1H, s),7.76(2H, d, J=8.8 Hz), 8.25(2H, d, J=8.8 Hz), 8.58(1H, s).

b)(5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), 14.2 mg of the title compound wasobtained from the whole amount of 4-nitrobenzyl(5R,6S)-2-(5,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide obtained above.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(3H, d, J=6.4 Hz), 2.77(3H, s), 3.32(2H,m), 3.55(1H, dd, J₁=6.2 Hz, J₂=3.0 Hz), 3.91(3H, s), 4.28(2H, m),7.37(1H, s), 7.83(1H, s).

Example 31 (1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl (1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 40.4 mg of4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 305 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 473 mg of5-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.33(3H, d, J=7.2 Hz), 1.38(3H, d, J=6.3 Hz), 3.37(1H,dd, J₁=6.1 Hz, J₂=2.8 Hz), 3.57(1H, m), 4.34(2H, m), 4.73(2H, d, J=6.3Hz), 5.29(1H, d, J=13.7 Hz), 5.53(1H, d, J=13.7 Hz), 6.94(1H, s),6.96(1H, br.s), 7.66(2H, d, J=8.8 Hz), 8.21(2H, d, J=8.8 Hz), 8.26(1H,s), 8.33(1H, s).

b) (1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 44.3 mg of the title compound.was obtained from 160 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.25(3H, d, J=7.2 Hz), 1.31(3H, d, J=6.4Hz), 3.55(1H, dd, J₁=6.0 Hz, J₂=2.7 Hz), 3.64(1H, m), 4.27(1H, m),4.34(1H, dd, J₁=9.3 Hz, J₂=2.7 Hz), 4.92(2H, d, J=2.7 Hz), 7.37(1H, s),8.07(1H, s), 8.25(1H, s).

Example 32 Pivaloylmethy (1S,5R,6S)-2-(5formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 31.2 mg of the title compound wasobtained from 34.7 mg of(1S,5R,6S)-2-(5-formylamino-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.19(9H, s), 1.31(3H, d, J=7.3 Hz), 1.35(3H, d, J=6.2Hz), 3.34(1H, dd, J₁=6.0 Hz, J₂=2.9 Hz), 3.56(1H, m), 4.32(2H, m),4.77(2H, m), 5.86(1H, d, J=5.6 Hz), 5.97(1H, d, J=5.6 Hz), 6.94(1H, s),7.08(1H, br.s), 8.26(1H, s), 8.28(1H, s).

Example 33(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was obtained from 50.4 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.1 Hz), 1.26(3H, d, J=7.1 Hz), 3.50(1H,dd, J₁=5.2 Hz, J₂=3.0 Hz), 3.76(1H, m), 4.05(3H, s), 4.07(1H, m),4.41(1H, dd, J₁=10.0 Hz, J₂=3.0 Hz), 4.88(2H, m), 5.19(1H, d, J=4.9 Hz),5.41(1H, d, J=13.8 Hz), 5.52(1H, d, J=13.8 Hz), 7.73(2H, d, J=8.9 Hz),7.79(iH, s), 8.14(1H, s), 8.22(2H, d, J=8.9 Hz), 8.64(1H, s), 8.83(1H,m).

b)(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), 22.2 mg of the title compound wasobtained from the whole amount of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide.

NMR (D₂O) δ (HOD=4.80 ppm): 1.28(3H, d, J=7.2 Hz), 1.31(3H, d, J=6.4Hz), 3.56(1H, m), 3.67(1H, m). 4.05(3H, s), 4.28(1H, m), 4.34(1H, m),4.95(2H, d, J=3.8 Hz), 7.50(1H, s), 8.16(1H, s), 8.20(1H, s).

Example 34(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(5-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 799 mg of 4-nitrobenzyl(1S,5R,6)-2-(5-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 724 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.34 g of 5-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.08(3H, s), 0.09(3H, s), 0.89(9H, s), 1.31(3H, d, J=7.4Hz), 1.40(3H, d, J=6.3 Hz), 3.36(1H, dd, J₁=6.6 Hz, J₂=2.7 Hz), 3.49(1H,m), 4.34(2H, m), 4.97(2H, s), 5.26(1H, d, J=13.7 Hz), 5.51(1H, d, J=13.7Hz), 6.94(1H, s), 7.67(2H, d, J=8.8 Hz), 8.23(2H, d, J=8.8 Hz), 8.35(1H,s).

b) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 799 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 20 ml of THF were added 1.1 ml of acetic acid and 6.5 ml of 1 Msolution of tetra-n-butylammonium fluoride in THF under the atmosphereof argon, and the mixture was stirred at room temperature for 30minutes. The reaction mixture was concentrated under reduced pressure,and diluted with 100 ml of ethyl acetate, 100 ml of aqueous saline and asaturated aqueous sodium hydrogen carbonate solution to adjust pH to7.8. The organic layer was separated, washed with aqueous saline, driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure. The residue thus obtained was purified by columnchromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 619mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.19(3H, d, J=6.3 Hz), 2.23(3H, d, J=7.2 Hz), 3.40(1H,dd, J1=5.8 Hz, J2=2.7 Hz), 3.69(1H, m), 4.04(1H, m), 4.33(1H, dd, J1=9.7Hz, J2=2.8 Hz), 4.68(2H, d, J=5.8 Hz), 5.14(1H, d, J=5.2 Hz), 5.38(1H,d, J=14.3 Hz), 5.49(1H, t, J=5.8 Hz), 5.51(1H, d, J=14.3 Hz), 6.92(1H,s), 7.73(2H, d, J=8.5 Hz), 8.21(2H, d, J=8.5 Hz), 8.36(1H, s).

c)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 57.8 mg of the title compound wasobtained from 200 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.26(3H, d₇ J=7.6 Hz), 1.32(3H, d, J=6.1Hz), 3.54(1H, m), 3.63(1H, m), 4.30(2H, m), 4.97(2H, m), 7.18(1H, s),7.98(1H, s).

Example 35 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 20.3 mg of the title compound wasobtained from 39.6 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.18(9H, s), 1.28(3H, d, J=7.4 Hz), 1.36(3H, d, J=6.3Hz), 3.33(1H, dd, J₁=6.5 Hz, J₂=2.7 Hz), 3.47(1H, m), 4.31(2H, m),4.95(2H, s), 5.87(1H, d, J=5.6 Hz), 5.97(1H, d, J=5.6 Hz), 6.96(1H, s),8.26(1H, s).

Example 36(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(3-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 146 mg of 4-nitrobenzyl(1S,5R,6S)-2-(3-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 256 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 346 mg of3-(t-butyldimethylsilyloxy)methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.01(3H, s), 0.06(3H, s), 0.85(9H, s), 1.22(3H, d, J=7.4Hz), 1.39(3H, d, J=6.2 Hz), 3.40(1H, m), 4.34(1H, m), 4.44(1H, m),4.45(1H, d, J=13.4 Hz), 4.59(1H, d, J=13.4 Hz), 5.19(1H, d, J=13.7 Hz),5.40(1H, d, J=13.7 Hz), 7.08(1H, s), 7.52(2H, d J=8.9 Hz), 8.09(1H, s),8.15(2H, d, J=8.9 Hz).

b) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 34-b), 75.9 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 200 mg of 4-nitrobenzyl(1S,5R,6S)-2-(3-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR(CDCl3) δ: 1.16(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3 Hz), 3.42(2H, m),4.32(1H, m), 4.46(1H, dd, J₁=10.4 Hz, J₂=3.1 Hz), 4.54(1H, d, J=13.6Hz), 4.61(1H, d, J=13.6 Hz), 5.22(1H, d, J=13.4 Hz), 5.44(1H, d, J=13.4Hz), 7.07(1H, s), 7.56(2H, d, J=8.5 Hz), 8.18(2H, d, J=8.5 Hz), 8.20(1H,s).

c)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 11.4 mg of the title compound wasobtained from 5.9 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.18(3H, d, J=6.9 Hz), 1.32(3H, d, J=6.4Hz), 3.44(1H, m), 3.61(1H, m), 4.30(1H, m), 4.42(1H, m), 7.61(1H, s),9.19(1H, s).

Example 37(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 406 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 543 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 780 mg of 7-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.16(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3 Hz), 2.29(3H,s), 3.46(1H, dd, J₁=6.0 Hz, J₂=3.2 Hz), 3.63(1H, m), 4.33(1H, m),4.51(1H, dd, J₁=10.4 Hz, J₂=3.2 Hz), 5.13(1H, d, J=13.4 Hz), 5.31(1H, d,J=13.4 Hz), 6.92(1H, s), 7.36(2H, d, J=8.5 Hz), 7.75(1H, s), 8.14(2H, d,J=8.5 Hz).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 79.1 mg of the title compound wasobtained from 200 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.14(3H, d, J=7.4 Hz), 1.31(3H, d, J=6.4Hz), 2.42(3H, s), 3.55(1H, m), 3.60(1H, dd, J₁=5.9 Hz, J₂=3.0 Hz),4.30(1H, m), 4.42(1H, dd, J₁=10.0 Hz, J₂=3.0 Hz), 7.37(1H, s), 8.60(1H,s).

Example 38 Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 758 mg of 4-nitro-benzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas obtained as an orange amorphous from 934 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapen-2-em-3-carboxylateand 1.375 g of 7-methyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.40(3H, d, J=6.3 Hz), 2.1(1H, br.s), 2.33(3H, s),3.29-3.36(3H, m), 4.25-4.38(2H, m), 5.31(1H, d, J=13.7 Hz), 5.54(1H, d,J=13.7 Hz), 7.69(2H, d, J=6.9 Hz), 7.93(1H, s), 8.14(1H, s), 8.24(2H, d,J=6.9 Hz). MS (TSP): 469 (M⁺+H).

b) Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d) described below except that 328mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate,and purification was carried out with CHP-20P (2% THF in water), 111.4mg of the title compound was obtained.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.3 Hz), 2.37(3H, s),3.31-3.34(2H, br.s, t), 3.53-3.55(1H, m), 4.22-4.35(2H, m), 7.82(1H, s),8.70(1H, s). MS (TSP): 356 (M⁺+Na), 334 (M⁺+H).

Example 39 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135 described below, 29.1 mg of thetitle compound was obtained as a yellow powder from 51.4 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.22(9H, s), 2.33(3H, s), 3.22-3.34(3H, m), 4.24-4.35(2H,m), 5.90(1H, d, J=5.6 Hz), 6.00(1H, d, J=5.6 Hz), 7.94(1H, s), 8.18(1H,s). MS (TSP): 448 (M⁺+H).

Example 40 Pivaloylmethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 28.3 mg of the title compound wasobtained from 39.5 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.12(3H, d, J=7.2 Hz), 1.16(9H, s), 1.36(3H, d, J=6.2Hz), 2.34(3H, s), 3.41(1H, dd, J₁=6.5 Hz, J₂=3.2 Hz), 3.70(1H, m),4.31(1H, m), 4.47(1H, dd, J₁=10.4 Hz, J₂=3.2 Hz), 5.73(1H, d, J=5.5 Hz),5.86(1H, d, J=5.5 Hz), 7.03(1H, s), 7.78(1H, s).

Example 41(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 14 except that the reaction was carriedout for 3 days, 19.3 mg of the title compound was obtained from 100 mgof 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.26(3H, d, J=6.9 Hz), 1.32(3H, d, J=6.1Hz), 3.56(1H, m), 3.66(1H, m), 4.05(3H, s), 4.30(2H, m), 5.13(2H, s),7.51(1H, s), 8.14(1H, s).

Example 42(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 64.0 mg of 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide was prepared as a yellowish orange oil by using 93.7 mg of4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CD₃OD) δ: 1.31(3H, d, J=6.3 Hz), 2.49(3H, s), 3.45-3.55(3H, m),4.01(3H, s), 4.10-4.25(1H, m), 4.30-4.40(1H, m), 5.40(1H, d, J=13.5 Hz),5.55(1H, d, J=13.5 Hz), 7.76(2H, d, J=9 Hz), 8.24(2H, d, J=9.0 Hz),8.38(1H, s), 9.25(0.2H, s, exchanged with CD₃OD). MS (TSP): 483 (M⁺).

b)(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

The title compound was obtained in a yield of 7.2 mg as a yellowamorphous from 61.0 mg of 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatein the same manner as in Example 4-b) except that purification wascarried out on CHP-20P (2% THF in water) and COSMOSEAL 40C18-PREP(water:methanol=20:1-10:1).

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.3 Hz), 2.41(3H, s),3.24-3.40(2H, m), 3.51-3.55(1H, m), 3.92(3H, s), 4.22-4.28(2H, m),7.86(1H, m), 9.04(0.5H, s, exchanged with D₂O). MS( ).

Example 43(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 608 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 696 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and1.05 g of 7-methyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.39(3H, d, J=6.3 Hz), 2.30(3H, s), 3.35(3H, m), 4.31(1H,m), 4.43(1H, m), 5.21(1H, d, J=13.3 Hz), 5.34(1H, d, J=13.3 Hz),7.01(1H, s), 7.42(2H, d, J=8.9 Hz), 7.67(1H, s), 8.16(2H, d, J=8.9 Hz).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 45.5 mg from 306 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.1 Hz), 2.48(3H, s), 3.25(1H,dd, J₁=17.2 Hz, J₂=10.0 Hz), 3.47(1H, dd, J₁=17.2 Hz, J₂=8.4 Hz),3.61(1H, m), 4.29(1H, m), 4.40(1H, m), 7.47(1H, s), 8.73(1H, s).

Example 44 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 37.8 mg from 62.6 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.19(9H, s), 1.38(3H, d, J=6.2 Hz), 2.34(3H, s), 3.35(3H,m), 4.28(1H, m), 4.40(1H, m), 5.78(1H, d, J=5.5 Hz), 5.88(1H, d, J=5.5Hz), 7.09(1H, s), 7.71(1H, s).

Example 45(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide was obtained from 103 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.2 Hz), 2.39(3H, s), 3.30(2H, m),3.55(1H, m), 3.88(3H, s), 4.04(1H, m), 4.33(1H, m), 5.22(1H, d, J=13.7Hz), 5.31(1H, d, J=13.7 Hz), 7.53(2H, d, J=8.7 Hz), 7.84(1H, s),8.20(2H, d, J=8.7 Hz), 9.57(1H, s).

b)(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), the title compound was obtainedin a yield of 24.9 mg from the whole amount of 4-nitrobenzyl(5R,6S)-2-(6,7-dimethylimidazo[5,1-b]thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide obtained above.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.5 Hz), 2.45(3H, s), 3.22(1H,dd, J₁=17.6 Hz, J₂=10.2 Hz), 3.44(1H, dd, J₁=17.6 Hz, J₂=8.8 Hz),3.58(1H, dd, J₁=5.8 Hz, J₂=2.8 Hz), 3.94(3H, s), 4.26(1H, m), 4.37(1H,m), 7.44(1H, s), 8.85(1H, s).

Example 46(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 622 mg from 696 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and1.14 g of 3-methyl-2-(tri-n-butyl-stannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.39(3H, d, J=6.3 Hz), 2.20(3H, s), 3.20(2H, m), 3.35(1H,dd, J₁=6.4 Hz, J₂=2.9 Hz), 4.31(1H, m), 4.40(1H, m), 5.24(1H, d, J=13.7Hz), 5.42(1H, d, J=13.7 Hz), 7.09(1H, s), 7.54(2H, d, J=8.4 Hz),7.86(1H, s), 8.15(2H, d, J=8.4 Hz).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 94.6 mg from 329 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.5 Hz), 2.37(3H, s), 3.15(1H,dd, J₁=17.3 Hz, J₂=10.2 Hz), 3.32(1H, dd, J₁=17.3 Hz, J₂=8.3 Hz),3.58(1H, dd, J₁=5.8 Hz, J₂=3.0 Hz), 4.26(1H, m), 4.37(1H, m), 7.52(1H,s), 9.06(1H, s).

Example 47 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 38.6 mg of the title compound wasobtained from 61.4 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.11(9H, s), 1.37(3H, d, J=6.3 Hz), 2.30(3H, s), 3.19(2H,m), 3.31(1H, dd, J₁=6.5 Hz, J₂=2.9 Hz), 4.28(1H, m), 4.36(1H, m),5.80(1H, d, J=5.5 Hz), 5.90(1H, d, J=5.5 Hz), 7.08(1H, s), 7.93(1H, s).

Example 48 Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

a)(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidine)methyl]-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-[(pyridine-2-yl)thiocarbonyl]ethyl]azetidin-2-one

To the ice-cooled mixture of 6.6 g of(3S,4R)-1-[(allyoxy-carbonyl)(triphenylphosphoranylidine)methyl]-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-(carboxy)ethyl]azetidin-2-oneand 2.75 g of triphenylphosphine in 30 ml of acetonitrile was added 2.31g of 2,2′-dipyridyl disulfide under the atmosphere of argon, and themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure, and purified by columnchromatography on silica gel (hexane:ethyl acetate=3:1) to give 5.2 g of(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidine)methyl]-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-[(pyridine-2-yl)thiocarbonyl]ethyl]azetidin-2-one.

NMR (CDCl₃) δ: −0.15(3H, s), −0.07(3H, s), 0.80(9H, s), 0.97(3H, d,J=6.1 Hz), 1.13(3H, d, J=7.1 Hz), 2.25-2.35(1H, m), 2.60-2.67(2H, m),3.16(1H, m), 4.15-4.30(1H, m), 4.60-4.75(2H, m), 5.10-5.22(1H, m),7.50-7.80(19H, m).

b) Ally(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To an ice-cooled solution of 0.61 g of 5-bromoimidazo[5,1-b]thiazole in6 ml of THF was added 3.2 ml of 1 M solution of ethyl magnesium bromidein THF. After stirring at room temperature for 2 hours, the mixture wascooled to −50° C., and a solution of 2.23 g of(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-[(pyridin-2-yl)thiocarbonyl]ethyl]azetidin-2-onein 6 ml of THF was added. The mixture was stirred for 1 hour duringwhich the temperature was raised up to 10° C. The reaction mixture wasdiluted with 12 ml of a saturated aqueous ammonium chloride solution,extracted with dichloromethane, and the organic layer was dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue thus obtained was purified by columnchromatography on silica gel (hexane:ethyl acetate=3:2) to give 0.67 gof crude product. A 0.63 g portion of the crude product and a solutionof 4.5 mg of hydroquinone in 7 ml of xylene were stirred under heatingat 140° C. for 6 hours. The reaction mixture was diluted with 30 ml ofethyl acetate, washed with saturated aqueous sodium hydrogen carbonate,and saturated aqueous saline in this sequence, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue thus obtained was purified by column chromatography onsilica gel (hexane:ethyl acetate=2:1) to give 0.35 g of allyl(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 0.12(6H, s), 0.90(9H, s), 1.12(3H, d, J=7.4 Hz), 1.29(3H,d, J=6.1 Hz), 3.32(1H, dd, J=2.9, 6.4 Hz), 3.81-3.91(1H, m),4.23-4.35(2H, m), 4.62-4.78(2H, m), 5.18-5.38(2H, m), 5.79-5.93(1H, m),6.90(1H, d, J=4.2 Hz), 7.17(1H, d, J=4.2 Hz), 7.31(1H, s).

c) Allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 0.35 g of allyl(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazole-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 12 ml of THF was added under ice-cooling 0.66 ml of acetic acid and2.9 ml of a 1 M solution of tetra-n-butyl-ammonium fluoride in THF, andthe mixture was stirred at room temperature for 36 hours. The reactionmixture was diluted with 50 ml of ethyl acetate, washed with saturatedaqueous sodium hydrogen carbonate and saturated aqueous saline in thissequence, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue thus obtained waspurified by column chromatography on silica gel (ethyl acetate) to give0.16 g of allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.17(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3 Hz), 3.38(1H,dd, J=2.9, 6.6 Hz), 3.82-3.92(1H, m), 4.25-4.35(1H, m), 4.39(1H, dd,J=2.9, 10.0 Hz), 4.60-4.78(1H, m), 5.18-5.34(2H, m), 5.77-5.90(1H, m),6.91(1H, d, J=4.3 Hz), 7.15(1H, d, J=4.3 Hz), 7.31(1H, s).

d) Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 40 mg of allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.8 ml of dichloromethane and 0.8 ml of ethyl acetate were addedunder the atmosphere of argon 3.4 mg of triphenylphosphine, 29 mg ofpotassium 2-ethylhexanoate, 6.4 mg of tetrakis-triphenylphosphinepalladium (0), and the mixture was stirred at room temperature for 1hour. The reaction mixture was poured into diethyl ether, and theresulting precipitate was collected by filtration, and purified bycolumn chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1) togive 13 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.10(3H, d, J=7.2 Hz), 1.31(3H, d, J=6.4Hz), 3.50-3.65(2H, m), 4.25-4.37(2H, m), 7.10(1H, d, J=4.3 Hz), 7.22(1H,s), 7.38(1H, d, J=4.3 Hz).

Example 49(1S,5R,6S)-2-(7-formylaminomethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

To a solution of 134 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 2 ml of DMF was added 1.6 ml of methyl iodide, and the mixture wasstirred at room temperature for 12 hours. The solvent was removed underreduced pressure. The residue thus obtained was dissolved in 5 ml of THFand 5 ml of 0.1 M sodium phosphate buffer (pH 6.8), and 150 mg of 10%Pd-C. The reactor was purged with hydrogen, the reaction mixture wasstirred at room temperature for 1 hour. The catalyst was collected byfiltration, and washed with a mixed solution of 2 ml of 0.1 M sodiumphosphate buffer (pH 6.8) and 2 ml of THF. The filtrate was washed with10 ml of ethyl acetate, and the aqueous layer obtained was purified bycolumn chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1). Thefraction containing the aimed product was concentrated under reducedpressure, and then lyophilized to give 58 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=7.2 Hz), 1.30(3H, d, J=6.4Hz), 3.52-3.68(2H, m), 4.01(3H, s), 4.23-4.35(2H, m), 4.68(2H, s),8.09(1H, s), 8.26(1H, s), 9.15(1H, s).

Example 50 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 40 mg of potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.8 ml of DMF was added at −30° C. 30 mg of pivaloyloxymethyl iodide,and the mixture was stirred for 1 hour during which the temperature wasraised up to room temperature. The reaction mixture was diluted with 30ml of dichloromethane, washed with semi-saturated aqueous saline, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue thus obtained was purified by columnchromatography on silica gel (ethyl acetate:methanol=4:1) to give 54 mgof the title compound.

NMR (CDCl₃) δ: 1.17(3H, d, J=7.0 Hz), 1.20(9H, s), 1.37(3H, d, J=6.3Hz), 3.38(1H, dd, J=2.9, 6.6 Hz), 3.85-3.95(1H, m), 4.25-4.33(1H, m),4.38(1H, dd, J=2.9, 10.0 Hz), 5.78(1H, d, J=5.5 Hz), 5.96(1H, d, J=5.5Hz), 6.95(1H, d, J=4.2 Hz), 7.15(1H, d, J=4.2 Hz), 7.34(1H, s).

Example 51(5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 14, 4.6 mg of the title compound wasobtained from 109 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(3H, d, J=6.5 Hz), 2.36(3H, s), 3.15(1H,dd, J₁=17.1 Hz, J₂=9.8 Hz), 3.32(1H, dd, J₁=17.1 Hz, J₂=8.3 Hz),3.59(1H, m), 4.09(3H, s), 4.28(1H, m), 4.38(1H, m), 7.57(1H, s),9.20(1H, s).

Example 52 Acetoxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 1 ml of DMF was added 32 mg of acetoxymethyl bromide under theatmosphere of argon at −20° C., and the mixture was stirred for 3 hoursduring which the temperature was raised up to −10° C. The reactionmixture was extracted twice with 20 ml of ethyl acetate, and the organiclayer was washed twice with 10 ml of semi-saturated aqueous saline,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to a volume of 2 ml. The residue thus obtained waspurified by column chromatography on silica gel(chloroform:methanol=9:1) and on Sephadex LH-20(dichloromethane:methanol=1:1) in this sequence to give 11 mg of thetitle compound.

NMR (CDCl₃) δ: 1.29(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3 Hz), 2.13(3H,s), 3.31-3.51(2H, m), 4.27-4.39(2H, m), 5.88, 5.96(2H, AB, J=5.7 Hz),7.08(1H, s), 8.06(1H, s), 8.38(1H, s). MS (TSP): 406 (M⁺+H).

Example 53 1-(acetoxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer-mixture)

In the same manner as in Example 52, 11 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 45 mg of 1-(acetoxy)ethyl iodide.

NMR (CDCl₃) δ: 1.27, 1.28(total 3H, d each, J=7.1 Hz), 1.37, 1.38(total3H, d each, J=6.0 Hz), 1.56, 1.61(total 3H, d each, J=5.5 Hz), 2.06,2.13(total 3H, s each), 3.09-3.49(2H, m), 4.26-4.42(2H, m),7.01-7.07(2H, m), 8.05(1H, s), 8.41(1H, s).

Example 54 (1-methylcyclohexan-1-yl)carbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 42 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 39 mg of (1-methylcyclohexan-1-yl)carbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.14(3H, s), 1.28(3H, d, J=7.1 Hz), 1.36(3H, d, J=6.1Hz), 1.17-1.60(8H, m), 1.95-2.05(2H, m), 3.29-3.50(2H, m), 4.25-4.40(2H,m), 5.92, 5.97(2H, AB, J=5.5 Hz), 7.07(1H, s), 8.07(1H, s), 8.33(1H, s).

Example 55 1-(ethoxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 39 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 68 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.27-1.39(9H, m), 1.59, 1.65(total 3H, d each, J=5.5 Hz),3.30-3.49(2H, m), 4.15-4.45(4H, m), 6.91-7.00(1H, m), 7.07(1H, s),8.04(1H, s), 8.41, 8.42(total 1H, s each). MS (TSP): 450 (M⁺+H).

Example 56 1-(isopropoxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 30 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateSodium and 71 mg of 1-(isopropoxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.26-1.39(12H, m), 1.59, 1.65(total 3H, d each, J=5.5Hz), 3.29-3.49(2H, m), 4.26-4.35(2H, m), 4.84-5.00(1H, m), 6.91-6.98(1H,m), 7.07(1H, m), 8.03(1H, s), 8.43(1H, s). MS (TSP): 464 (M⁺+H).

Example 57 1-(cyclohexyloxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 30 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 62 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.28, 1.29(total 3H, d each, J=7.4 Hz), 1.36, 1.38(total3H, d each, J=6.4 Hz), 1.59, 1.65(total 3H, d each, J=5.4 Hz),1.15-2.05(8H, m), 3.29-3.49(2H, m), 4.26-4.35(2H, m), 4.57-4.75(1H, m),6.92-6.98(1H, m), 7.07(1H, s), 8.03(1H, s), 8.42, 8.43(total 1H, seach). MS (TSP): 504(M⁺+H).

Example 58 Cyclohexyloxycarbonyloxy methyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 46 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 59 mg of cyclohexyloxycarbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.28(3H, d, J=7.4 Hz), 1.37, (3H, d, J=6.2 Hz),1.20-1.60(4H, m), 1.68-1.80(2H, m), 1.82-1.98(2H, m), 3.30-3.50(2H, m),4.25-4.40(2H, m), 4.61-4.70(1H, m), 5.90, 5.96(2H, AB, J=5.8 Hz),7.08(1H, s), 8.05(1H, s), 8.41(1H, s).

Example 59 3-phthalidyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 38 mg of the title compound wasobtained from 44 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 32 mg of 3-phthalidyl bromide.

NMR (CDCl₃) δ: 1.25-1.40(6H, m), 3.30-3.60(2H, m), 4.21-4.35(2H, m),7.07, 7.10(total 1H, s each), 7.46, 7.47(total 1H, s each),7.62-7.86(4H, m), 8.01, 8.06(total 1H, s each), 8.25, 8.51(total 1H, seach). MS (TSP): 466 (M⁺+H).

Example 60 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 37 mg of the title compound wasobtained from 49 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 53 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide.

NMR (CDCl₃) δ: 1.29(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3 Hz), 2.22(3H,s), 3.32-3.52(2H, m), 4.25-4.45(2H, m), 5.01, 5.08(2H, AB, J=14.0 Hz),7.08(1H, s), 8.07(1H, s), 8.26(1H, s).

Example 61 1-[(cyclohexylmethoxy)carbonyloxy]ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, the title compound was obtained ina yield of 42.1 mg from 44.8 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 89.0 mg of 1-[(cyclohexylmethoxy)carbonyloxy]ethyl iodide.

NMR (CDCl3) δ: 0.85-1.00(2H, m), 1.10-1.20(2H, m), 1.20, 1.21(total 3H,d each, J=7.2 Hz), 1.28, 1.31(total 3H, d each, J=6.2 Hz), 1.53(3H, d,J=5.5 Hz), 1.58(3H, d, J=5.5 Hz), 1.60-1.75(4H, m), 1.98-2.10(4H, m),3.25-3.28(1H, m), 3.34-3.42(1H, m), 3.88-3.96(2H, m), 4.78-4.30(2H, m),6.83-6.90(1H, m), 7.02(1H, s), 8.02(1H, s), 8.35-8.36(1H, m). MS (TSP):518 (M⁺+H).

Example 62 1-[(2-methylcyclohexan-1-yl)oxycarbonyloxy]ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 59.6 mg of the title compound wasobtained from 61.7 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 89.0 mg of 1-[(2-methylcyclohex-1-yl)oxycarbonyloxy]ethyl iodide.

NMR (CDCl₃) δ: 0.80-0.93(4H, m), 1.20, 1.21(total 3H, d each, J=7.4 Hz),1.28, 1.30(total 3H, d each, J=6.3 Hz), 1.52, 1.58(total 3H, d each,J=5.5 Hz), 1.58(3H, d, J=5.5 Hz), 1.62-1.73(2H, m), 1.90-2.15(4H, m),3.23-3.28(1H, m), 3.35-3.42(1H, m), 3.42(3H, s), 4.18-4.30(3H, m),6.83-6.92(1H, m), 7.01(1H, s), 8.01(1H, s), 8.32-8.37(1H, m). MS (TSP):518 (M⁺+H).

Example 63 Cyclopentyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 54.4 mg of the title compound wasobtained from 61.6 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 69.7 mg of cyclopentyloxycarbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.21(3H, d, J=7.1 Hz), 1.29(3H, d, J=6.1 Hz),1.48-1.58(2H, m), 1.63-1.85(5H, m), 3.25-3.30(1H, m), 3.35-3.42(1H, m),4.20-4.38(4H, m), 5.00-5.08(1H, m), 5.82(1H, d, J=5.7 Hz), 5.88(1H, d,J=5.7 Hz), 7.00(1H, s), 7.99(1H, s), 8.32(1H, s). MS (TSP): 476 (M⁺+H).

Example 64 (Z)-2-(3-phthalidylidene)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 36.8 mg of the title compound wasobtained from 58.0 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 81.2 mg of (Z)-3-(2-bromoethylidene)phthalide.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.3 Hz), 1.38(3H, d, J=6.2 Hz),3.33-3.50(3H, m), 4.29-4.38(2H, m), 5.18-5.30(2H, m), 5.80-5.85(1H, m),7.08(1H, s), 7.21-7.26(2H, m), 7.91-7.95(1H, m), 8.06(1H, s), 8.39(1H,s). MS (TSP): 492 (M⁺+H).

Example 65 (1R,2S,5R)-(1)-menthyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 80.4 mg of the title compound wasobtained from 64.4 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 92.5 mg of (1R,2S,5R)-(1)-menthyloxycarbonyloxymethyl iodide.

NMR (CDCl₃) δ: 0.67(3H, d, J=6.9 Hz), 0.79(3H, d, J=6.9 Hz), 0.84(3H, d,J=6.6 Hz), 0.90-1.05(2H, m), 1.22(3H, d, J=7.5 Hz), 1.30(3H, d, J=6.3Hz), 1.38-1.45(1H, m), 1.56-1.65(2H, m), 1.80-1.93(3H, m), 2.00-2.08(1H,m), 3.22-3.28(1H, m), 3.33-3.45(1H, m), 4.19-4.30(2H, m), 4.42-4.51(1H,m), 5.83(1H, d, J=5.8 Hz), 5.90(1H, d, J=5.8 Hz), 7.00(1H, s), 7.98(1H,s), 8.33(1H, s). MS (APCI): 546 (M⁺+H).

Example 66 (1S,2R,5S)-(d)-menthyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 89.2 mg of the title compound wasobtained from 61.7 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 90.0 mg of (1S,2R,5S)-(d)-menthyloxycarbonyloxynethyl iodide.

NMR (CDCl₃) δ: 0.70(3H, d, J=7.1 Hz), 0.81(3H, d, J=7.2 Hz), 0.83(3H, d,J=7.1 Hz), 0.90-1.05(2H, m), 1.21(3H, d, J=7.1 Hz), 1.29(3H, d, J=6.0Hz), 1.32-1.43(1H, m), 1.55-1.62(2H, m), 1.80-2.03(4H, m), 3.23-3.28(1H,m), 3.36-3.42(1H, m), 4.18-4.30(2H, m), 4.41-4.52(1H, m), 5.83(1H, d,J=5.8 Hz), 5.90(1H, d, J=5.8 Hz), 7.00(1H, s), 7.98(1H, s), 8.33(1H, s).MS (APCI): 546 (M⁺+H).

Example 67 1-(phenyloxycarbonyloxy)ethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 43.3 mg of the title compound wasobtained from 63.8 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 268.6 mg of 1-(phenyloxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.25-1.35(3H, m), 1.38-1.45(3H, m), 1.67, 1.73(total 3H,d each, J=5.5 Hz), (5H, m), 3.32-3.50(1H, m), 4.25-4.40(2H, m),7.00-7.06(1H, m), 7.07(1H, s), 7.18-7.42(5H, m), 8.04(1H, s), 8.41(1H,s). MS (TSP): 498 (M⁺+H).

Example 68 Phenyloxycarbonyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 52, 79.0 mg of the title compound wasobtained from 63.5 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 101.9 mg of phenyloxycarbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.24(3H, d, J=7.1 Hz), 1.34(3H, d, J=6.3 Hz),3.31-3.45(3H, m), 4.28-4.40(2H, m), 5.95(1H, d, J=5.8 Hz), 6.10(1H, d,J=5.8 Hz), 7.05(1H, s), 7.25-7.40(5H, m), 8.04(1H, s), 8.31(1H, s). MS(TSP): 484 (M⁺+H).

Example 69 1-(cyclohexyloxycarbonyloxy)-n-propyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 52, 60.0 mg of the title compound wasobtained from 61.3 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateand 100.8 mg of 1-(cyclohexyloxycarbonyloxy)-n-propyl iodide. NMR(CDCl₃) δ: 1.01, 1.08(total 3H, t each, J=7.4 Hz), 1.28, 1.30(total 3H,d each, J=7.1 Hz), 1.36, 1.39(total 3H, d each, J=6.6 Hz), 1.42-1.80(6H,m), 1.85-2.05(4H, m), 3.30-3.46(2H, m), 4.25-4.35(2H, m), 4.60-4.72(1H,m), 6.78-6.84(1H, m), 7.08(1H, s), 8.03(1H, s), 8.44, 8.46(total 1H, seach). MS (TSP): 518 (M⁺+H).

Example 70(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 92 mg of 4-nitrobenzyle(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 251 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 364 mg of 5-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=7.0 Hz), 1.20(3H, d, J=6.3 Hz), 3.42(1H,m), 3.72(1H, m), 4.04(1H, m), 4.34(1H, m), 5.14(1H, d, J=4.7 Hz),5.37(1H, d, J=13.8 Hz), 5.49(1H, d, J=13.8 Hz), 7.23(1H, s), 7.52(1H,br.s), 7.70(2H, d, J=8.2 Hz), 7.81(1H, br.s), 8.19(2H, d, J=8.2 Hz),8.71(1H, s).

b)(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 23.9 mg of the title compound wasobtained from 92 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=7.1 Hz), 1.33(3H, d, J=6.3Hz), 3.50(1H, m), 3.58(1H, m), 4.30(2H, m), 7.10(1H, s), 8.21(1H, s).

Example 71 Pivaloyloxymethyl(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 9.8 mg of the title compound wasobtained from 15.7 mg of(1S,5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.22(9H, s), 1.33(3H, d, J=7.2 Hz), 1.37(3H, d, J=6.3Hz), 3.35(1H, dd, J₁=6.3 Hz, J₂=2.7 Hz), 3.66(1H, m), 4.30(1H, m),4.37(1H, dd, j₁=9.5 Hz, J₂=2.7 Hz), 5.58(1H, br.s), 5.89(1H, d, J=5.5Hz), 5.99(1H, d, J=5.5 Hz), 7.00(1H, br.s), 7.15(1H, s), 8.73(1H, s).

Example 72 Potassium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate

a)(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethyl-ilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one

To a solution of 0.65 g of(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(carboxymethyl)azetidine-2-onein 4 ml of toluene were added under ice-cooling 0.14 ml of triethylamineand 0.12 ml of pivaloyl chloride, and the mixture was stirred at roomtemperature. The resulting precipitate was collected by filtration, andthe filtrate was purified by column chromatography on silica gel(hexane:ethyl acetate=2:1) to give 0.60 g of(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one.

NMR (CDCl₃) δ: −0.13(3H, s), −0.05(3H, s), 0.80(9H, s), 1.06(3H, d,J=6.0 Hz), 2.52-2.62(1H, m), 2.73-2.95(2H, m), 4.03-4.20(1H, m),4.40-4.67(2H, m), 5.10-5.35(2H, m), 5.87-5.98(1H, m), 7.43-7.85(15H, m).

b ) Allyl(5R,6S)-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 48-b), 0.31 g of allyl(5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylatewas obtained from -1.52 g of(3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one.

NMR (CDCl₃) δ: 0.10(6H, s), 0.90(9H, s), 1.28(3H, d, J=6.0 Hz), 3.22(1H,dd, J=2.9, 6.2 Hz), 3.35(1H, dd, J=8.8, 18.6 Hz), 3.60(1H, dd, J=10.0,18.6 Hz), 4.22-4.32(2H, m), 4.70-4.75(2H, m), 5.20-5.38(2H, m),5.80-5.94(1H, m), 6.91(1H, d, J=4.2 Hz), 7.12(1H, d, J=4.2 Hz), 7.30(1H,s).

c) Allyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 48-c), 72 mg of allyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylatewas obtained from 0.31 g of allyl(5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.40(3H, d, J=6.3 Hz), 3.30(1H, dd, J=3.0, 6.6 Hz),3.40(1H, dd, J=12.0, 18.7 Hz), 3.60(1H, dd, J=10.0, 18.7 Hz),4.24-4.36(2H, m), 4.64-4.82(2H, m), 5.20-5.36(2H, m), 5.81-5.94(1H, m),6.92(1H, d, J=4.2 Hz), 7.10(1H, d, J=4.2 Hz), 7.31(1H, s).

d) Potassium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 48-d), 49 mg of the title compound wasobtained from 172 mg of allyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.5 Hz), 3.22(1H, dd, J=10.1,17.8 Hz), 3.48(1H, dd, J=9.0, 17.8 Hz), 3.56(1H, dd, J=2.8, 5.8 Hz),4.25-4.44(2H, m), 7.11(1H, d, J=4.1 Hz), 7.19(1H, s), 7.27(1H, d, J=4.1Hz).

Example 73 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 50, 20 mg of the title compound wasobtained from potassium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.20(9H, s), 1.38(3H, d, J=6.4 Hz), 3.38(1H, dd, J=9.1,19.8 Hz), 3.60(1H, dd, J=9.9, 19.8 Hz), 4.23-4.48(2H, m), 5.84(1H, d,J=5.5 Hz), 5.95(1H, d, J=5.5 Hz), 6.96(1H, d, J=4.3 Hz), 7.13(1H, d,J=4.3 Hz), 7.33(1H, s).

Example 74(1S,5R,6S)-2-(5-fromylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a suspension of 292 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 20 ml of dichloromethane was added 936 mg of manganese dioxide, andthe mixture was stirred at room temperature for 2 days. The manganesedioxide was removed by filtration, and the filtrate was purified bycolumn chromatography on silica gel (dichloromethane:methanol=20:1) togive 148 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.36(3H, d, J=7.4 Hz), 1.40(3H, d, J=6.2 Hz), 3.40(1H,dd, J₁=6.4 Hz, J₂=2.9 Hz), 3.67(1H, m), 4.32(1H, m), 4.41(1H, dd, J₁=9.3Hz, J₂=2.9 Hz), 5.31(1H, d, J=13.4 Hz), 5.55(1H, d, J=13.4 Hz), 7.41(1H,s), 7.68(2H, d, J=8.8 Hz), 8.24(2H, d, J=8.8 Hz), 8.82(1H, s), 9.75(1H,s).

b)(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 34.7 mg of the title compound wasobtained from 115 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.23(3H, d, J=6.9 Hz), 1.34(3H, d, J=6.3Hz), 3.51(1H, m), 3.59(1H, m), 4.30(2H, m), 7.37(1H, s), 8.32(1H, s),9.40(1H, s).

Example 75 Pivaloyloxymethyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 33.2 mg of the title compound wasobtained from 40.0 mg of(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.22(9H, s), 1.34(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.2Hz), 3.37(1H, dd, J₁=6.4 Hz, J₂=2.9 Hz), 3.67(1H, m), 4.30(1H, m),4.39(1H, dd, J₁=9.6 Hz, J₂=2.9 Hz), 5.90(1H, d, J=5.6 Hz), 6.00(1H, d,J=5.6 Hz), 7.42(1H, s), 8.80(1H, s), 9.76(1H, s).

Example 76(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 392.6 mg of 4-nitrobenzy(1S,5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 598.9 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.03 g of7-t-butyldimethylsilyloxymethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.14, 0.16(total 6H, s each), 0.97, 1.09(total 9H, seach), 1.30(3H, d, J=7.2 Hz), 1.40(3H, d, J=6.2 Hz), 3.35-3.39(1H, m),3.43-3.51(1H, m), 4.28-4.40(2H, m), 4.88, 4.89(total 2H, s each),5.27(1H, d, J=14.0 Hz), 5.52(1H, d, J=14.0 Hz), 7.51(1H, s), 7.68(2H, d,J=8.9 Hz), 7.95(1H, s), 8.24(2H, d, J=8.9 Hz), 8.33(1H, s).

b) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 334.6 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 10 ml of THF were added 0.28 ml of acetic acid and 1.64 ml of a 1 Msolution of tetra-n-butylammonium fluoride in THF, and the mixture wasstirred at room temperature for 2.5 hours. After the reaction mixturewas adjusted to pH 8.2 with a saturated aqueous sodium hydrogencarbonate solution, it was extracted twice with ethyl acetate, andsemi-saturated aqueous saline. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue thus obtained was purified by columnchromatography on silica gel (ethyl acetate:methanol=9:1) to give 183 mgof 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxylmethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.29(3H, d, J=6.8 Hz), 1.39(3H, d, J=6.2 Hz),2.92-3.00(1H, m), 3.36(1H, dd, J₁=6.6 Hz, J₂=2.7 Hz), 3.38-3.50(1H, m),4.29-4.39(2H, m), 4.77(2H, s), 5.27(1H, d, J=13.8 Hz), 5.52(1H, d,J=13.8 Hz), 7.67(2H, d, J=8.9 Hz), 7.98(1H, s), 8.23(2H, d, J=8.9 Hz),8.31(1H, s).

c)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-²-yl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 87.7 mg of the title compound wasobtained from 139.9 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.25(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.3Hz), 3.50-3.61(2H, m), 4.24-4.32(2H, m), 4.66(2H, s), 7.89(1H, s),8.11(1H, s).

Example 77(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 68.1 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxateiodide was obtained from 54.5 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CD₃OD) δ: 1.22(3H, d, J=6.3 Hz), 1.26(3H, d, J=7.4 Hz), 3.24(3H,s), 3.60-3.68(1H, m), 3.96(2H, s), 4.03-4.12(1H, m), 4.31-4.36(1H, m),5.25(1H, d, J=13.7 Hz), 5.42(1H, d, J=13.7 Hz), 7.63(2H, d, J=8.8 Hz),8.11(2H, d, J=8.8 Hz), 8.42(1H, s), 9.29(1H, s).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), 16.9 mg of the title compound wasobtained from 68.1 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=7.2 Hz), 1.30(3H, d, J=6.3Hz), 3.51-3.67(3H, m), 4.01(2H, s), 4.21-4.33(3H, m), 4.86(2H, s),8.06(1H, s), 9.14(1H, s).

Example 78 Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

a)(3S,4R)-1-(allyloxycarbonyl)(triphenylphosphoranylidene)methyl-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-(imidazo[5,1-b]thiazol-7-yl-carbonyl)ethyl]-azetidine-2-one

To a solution of 540 mg of 7-iodoimidazo[5,1-b]thiazole in 16 ml of THFwas added 2.4 ml of a 1 M solution of ethylmagnesium bromide in THFunder ice-cooling under the atmosphere of argon, and the mixture wasstirred at room temperature for 30 minutes. After confirming theexhaustion of the starting materials, the reaction mixture was cooled to−35-−40° C., and a solution of 1.64 g of3S,4R)-1-(allyloxycarbonyl)(triphenylphosphoranylidene)methyl-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-(pivaloyloxycarbonyl)ethyl]-azetidine-2-onein 10 ml of THF was slowly added to the reaction mixture. After 15minutes, the reaction mixture was placed in an ice bath, and stirred for3 hours. It was diluted with 25 ml of a saturated ammonium, andextracted four times with 25 ml of ethyl acetate. The organic layer waswashed twice with 30 ml of saturated aqueous saline, dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue thus obtained was purified by columnchromatography on silica gel (hexane:ethyl acetate=1:4—ethyl acetate) togive 570 mg of(3S,4R)-1-(allyloxycarbonyl)(triphenylphosphoranylidene)methyl-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-(imidazo[5,1-b]thiazol-7-yl-1-carbonyl)ethyl]-azetidine-2-one.

NMR (CDCl₃) δ: −0.2-0.0(6H, m), 0.6-0.8(9H, m), 0.8-1.5(6H, m),2.7-3.4(3H, m), 4.0-4.7(3H, m), 5.0-5.4(2H, m), 5.8-6.0(1H, m), 7-8(18H,m).

b ) Allyl(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

To a solution of 276 mg of(3S,4R)-1-(allyloxycarbonyl)(triphenylphosphoranylidene)methyl-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-(imidazo[5,1-b]thiazol-7-yl-1-carbonyl)ethyl]-azetidine-2-onein 8 ml of xylene was added 8 mg of hydroquinone, and the mixture washeated to 125° C. After cooling, the reaction mixture was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1-1:3) togive 145 mg of allyl(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 0.10(6H, m), 0.90(9H, s), 1.20(3H, d, J=7.2 Hz), 1.32(3H,d, J=6.2 Hz) 3.25(1H, dd, J₁=6.9 Hz, J₂=2.6 Hz), 3.9-4.3(3H, m), 4.8(2H,m), 5.3-5.4(2H, m), 6.0(1H, m), 7.03(1H, d, J=4.3 Hz), 7.50(1H, d, J=4.3Hz), 8.10(1H, s).

c) Allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 460 mg of allyl(1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 14 ml of THF were added 860 μl and 3.76 ml of a 1 Mtetra-n-butylammonium fluoride in THF, and the mixture was stirred atroom temperature for 2 days. The reaction mixture was diluted with 120ml of ethy acetate, washed with 30 ml of semi-saturated aqueous saline,and then with 30 ml of a mixed solution of semi-saturated aqueous salineand a saturated aqueous sodium hydrogen carbonate solution (1:1), driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure. The residue thus obtained was purified by columnchromatography on silica gel (dichloromethane:methanol=97:3-95:5) togive 286 mg of allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.21(3H, d, J=7.2 Hz), 1.39(3H, d, J=6.3 Hz), 3.30(1H,dd, J₁=6.9 Hz, J₂=2.5 Hz), 4.0(1H, m), 4.2-4.4(2H, m), 4.83(2H, m),5.2-5.5(2H, m), 6.0(1H, m), 7.04(1H, d, J=4.3 Hz), 7.53(1H, d, J=4.3Hz), 8.12(1H, s).

d) Potassium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 117 mg of allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein a mixed solvent of 2.5 ml of dichloromethane and 2.5 ml of ethyacetate were added 8.1 mg of triphenylphosphine, 56.5 mg of potassium2-ethylhexanoate, and 11.8 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred under the atmosphere of argon at roomtemperature for 20 minutes. After confirming the exhaustion of thestarting materials, the reaction mixture was diluted with 10 ml of ethylacetate, extracted three or four times with water, and the aqueous layerwas concentrated under reduced pressure. The concentrate was purified bycolumn chromatography on COSMOSEAL 40C18-PREP to give the title compoundin a yield of 55 mg.

NMR (D₂O) δ (HOD=4.80 ppm): 1.13(3H, d, J=7.2 Hz), 1.34(3H, d, J=6.3Hz), 3.37(1H, dd, J₁=6.5 Hz, J₂=2 Hz), 3.53(1H, m), 4.17(1H, dd, J₁=8.6Hz, J₂=2 Hz), 4.26(1H, m), 7.17(1H, d, J=4.1 Hz), 7.69(1H, d, J=4.1 Hz),8.26(1H, s).

Example 79(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(6-methylimidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

To a solution of 77 mg of allyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-carbapen-2-em-3-carboxylatein dichloromethane was added dropwise 37 mg of trifluoromethanesulfonicacid under ice-cooling. After confirming the exhaustion of the startingmaterials, the solvent was removed under reduced pressure. The residuewas triturated with 2.4 ml of dichloromethane and 2.4 ml of ethylacetate, followed by about 1 ml of acetonitrile to form a homogeneoussolution, to which 5.2 mg of triphenylphosphine and 36.5 mg of potassium2-ethylhexanoate was added, followed bytetrakis(triphenylphosphine)palladium (0) for further 40 minute stirringat room temperature. The reaction mixture was diluted with 10 ml ofdichloromethane, and extracted twice with 20 ml of water. The aqueouslayer was concentrated, and the residue was purified by columnchromatography on DIAION HP-20 (water—water:acetone=10:1) and onCOSMOSEAL 40C18-PREP (water:acetonitrile=95:5-90:10) in this sequence togive 5.8 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.09(3H, d, J=7.4 Hz), 1.31(3H, d, J=6.5Hz), 2.58(1H, m), 3.5-3.7(2H, m), 3.96(3H, s), 4.30(1H, m), 4.45(1H, dd,J₁=10.2 Hz, J₂=3.0 Hz), 7.53(1H, d, J=4.2 Hz), 7.92(1H, d, J=4.2 Hz),9.31(1H, s).

Example 80 Sodium(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained as a yellow powder in a yield of 907 mg from 887 mg of4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapen-2-em-3-carboxylateand 1.254 g of 7-chloro-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=6.3 Hz), 3.40-3.50(2H, m), 3.52(1H, dd,J₁=6.1 Hz, J₂=3.1 Hz), 3.97-4.05(1H, m), 4.25(1H, dt, J₁=10.3 Hz, J₂=2.8Hz), 5.17(1H, d, J=4.9 Hz), 5.42(1H, d, J=13.7 Hz), 5.54(1H, d, J=13.7Hz), 7.76(2H, d, J=8.5 Hz), 8.22(1H, s), 8.25(2H, d, J=8.5 Hz), 8.36(1H,s). MS (TSP): 489 (M⁺+H).

b) Sodium(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d) except that purification wascarried out on CHP-20P (2% THF in water), 113 mg of the title compoundwas obtained from 245 mg of(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(1H, d, J=6.3 Hz), 3.21-3.25(2H, m),3.51(1H, dd, J₁=5.9 Hz, J₂=2.9 Hz), 4.20-4.26(2H, m), 7.71(1H, s),8.00(1H, s).

Example 81(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 108 mg of 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained from 170 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and267 mg of 5-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=6.3 Hz), 3.53(3H, m), 4.03(1H, m),4.27(1H, m), 5.15(1H, d, J=5.0 Hz), 5.42(1H, d, J=13.8 Hz), 5.54(1H, d,J=13.8 Hz), 7.23(1H, s), 7.53(1H, br.s), 7.76(2H, d, J=8.7 Hz), 7.83(1H,br.s), 8.24(2H, d, J=8.7 Hz), 8.63(1H, s).

b)(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), 34.7 mg of the title compound wasobtained from 105 mg of 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.33(3H, d, J=6.1 Hz), 3.28(2H, m), 3.53(1H,m), 4.28(2H, m), 7.10(1H, s), 8.00(1H, s).

Example 82 Pivaloyloxymethyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 12.2 mg of the title compound wasobtained from 35.8 mg of(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.24(9H, s), 1.37(3H, d, J=6.3 Hz), 3.33(1H, dd, J₁=6.3Hz, J₂=2.8 Hz), 3.46(2H, m), 4.30(2H, m), 5.60(1H, br.s), 5.91(1H, d,J=5.5 Hz), 6.03(1H, d, J=5.5 Hz), 6.98(1H, br.s), 7.13(1H, s), 8.56(1H,s).

Example 83(1S,5R,6S)-2-(5-formyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

To a suspension of 33 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 1 ml of dichloromethane was added 0.017 ml of methyltrifluoromethanesulfonate under ice-cooling. The mixture was stirred for5 hours, and concentrated under reduced pressure. The residualconcentrate was dissolved in 2 ml of THF and 2 ml of 1/15 M sodiumphosphate buffer (pH 6.6), and 47 mg of 10% Pd-C was added therto. Thereactor was purged with hydrogen, and the reaction mixture was stirredat room temperature for 2 hours. The catalyst was collected byfiltration on Celite, and washed with water. The filtrate was washedwith ethyl acetate, and the aqueous layer was purified by columnchromatography on DIAION HP-20 (20% methanol in water) and on COSMOSEAL40C18-PREP (water:methanol=10:1) to give 2.5 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.27(3H, d, J=6.9 Hz), 1.32(3H, d, J=6.3Hz), 3.57(1H, m), 3.64(1H, m). 4.07(3H, s), 4.29(1H, m), 4.35(IH, m),7.52(1H, s), 8.09(1H, s), 9.12(1H, s).

Example 84 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 27 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.5 ml of DMF was added 4.0 mg of sodium hydrogen carbonate, and themixture was cooled to −30° C. under the atmosphere of argon.Pivaloyloxymethyl iodide (30 mg) was added, and the reaction mixture wasstirred at −20-−30° C. for 1 hour. The reaction mixture was diluted with20 ml of ethyl acetate and 10 ml of semi-saturated aqueous saline, andthe mixture was stirred and separated. The organic layer was washed withsemi-saturated aqueous saline, dried over anhydrous magnesium sulfate,and the solvent was concentrated under reduced pressure to a volume ofabout 1 ml. It was purified by column chromatography on silica gel(ethyl acetate-ethyl acetate:methanol=97:3), and the solvent wasconcentrated under reduced pressure to a volume of about 0.5 ml andadded dropwise to isopropyl ether. The resulting precipitate wascollected by filtration, and desiccated under reduced pressure to give17 mg of the title compound.

NMR (CDCl₃) δ: 1.23(9H, s), 1.24(3H, d, J=7.9 Hz), 1.38(3H, d, J=6.3Hz), 3.29(1H, dd, J₁=6.6 Hz, J₂=2.5 Hz), 3.98(1H, m), 4.2-4.4(2H, m),5.96(1H, d, J=5.5 Hz), 6.05(1H, d, J=5.5 Hz), 7.02(1H, d, J=4.2 Hz),7.54(1H, d, J=4.2 Hz), 8.12(1H, s).

Example 85 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, 7.5 mg of the title compound wasobtained from 58.5 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.14(9H, s), 1.20(3H, d, J=7.4 Hz), 1.29(3H, d, J=6.2Hz), 3.25(1H, dd, J₁=6.6 Hz, J₂=2.7 Hz), 3.25-3.40(1H, m), 4.18-4.28(2H,m), 4.71(2H, s), 5.81(1H, d, J=5.6 Hz), 5.91(1H, d, J=5.6 Hz), 6.64(1H,s), 7.95(1H, s), 8.25(1H, s).

Example 86(5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-a) except that 98 mg of 4-nitrobenzyl(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateand a mixed solvent of dichloromethane and DMF (1:1), the crude4-nitrobenzyl(5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide was obtained as a yellowish brown oil in a yield of 99 mg.

In the same manner as in Example 4-b) except that a 61.0 mg portion ofthe crude product was used in the reaction, and purification was carriedout with CHP-20P (10% methanol in water), the title compound wasobtained in a yield of 7.5 mg as a pale yellow flocculate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.3 Hz), 3.30-3.45(2H, m),3.56(1H, dd, J₁=6.1 Hz, J₂=3.0 Hz), 4.00(3H, s), 4.22-4.35(2H, m),7.97(1H, s), 8.44(0.2H, s, partially exchanged with D₂O). MS (FAB⁺):370(M⁺+3), 368(M⁺+1).

Example 87 Pivaloyloxymethyl(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135, the title compound was obtained ina yield of 41 mg as a yellow powder from 58 mg of sodium(5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.22(9H, s), 1.36(3H, d, J=6.3 Hz), 3.25-3.35(3H, m),4.22-4.37(2H, m), 5.90(1H, d, J=5.6 Hz), 6.01(1H, d, J=5.6 Hz), 7.92(1H,s), 8.18(1H, s). MS (FAB⁺): 470(M⁺+3), 468(M⁺+1).

Example 88(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

To a suspension of 69 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylatein 2 ml of acetone was added 281 mg of iodoacetamide, and the mixturewas stirred at room temperature for 25 hours. The reaction mixture wasconcentrated under reduced pressure to dryness. The residue wastriturated with 3 ml of ethyl acetate, and the insolubles were collectedby filtration to give 4-nitrobenzyl(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.1 Hz), 3.45(3H, m), 4.03(1H, m),4.32(1H, m), 5.17(2H, s), 5.45(1H, d, J=13.8 Hz), 5.55(1H, d, J=13.8Hz), 7.08(1H, br.s), 7.63(1H, br.s), 7.75(2H, d, J=8.5 Hz), 7.83(1H, s),8.25(2H, d, J=8.5 Hz), 8.60(1H, s), 9.55(1H, s).

b)(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), the title compound was obtainedin a yield of 11.2 mg from the whole amount of 4-nitrobenzyl(5R,6S)-2-(6-carbamoylmethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.5 Hz), 3.32(2H, m), 3.54(1H,dd, J₁=5.6 Hz, J₂=2.8 Hz), 4.26(2H, m), 5.24(2H, s), 7.53(1H, s),7.94(1H, s).

Example 89 Sodium(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in example 5-a), 4-nitrobenzyl(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 365 mg as a dark yellow powder from 544 mg of4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapen-2-em-3-carboxylateand 728 mg of 5,7-dimethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.6 Hz), 1.21(3H, d, J=7.8 Hz), 2.14(3H,s), 2.45(3H, s), 3.34-3.41(1H, m), 3.65-3.77(1H, m), 3.97-4.05(1H, m),4.30(1H, dd, J₁=9.5 Hz, J₂=2.6 Hz), 5.15(1H, d, J=5.0 Hz), 5.37(1H, d,J=13.8 Hz), 5.50(1H, d, J=13.8 Hz), 7.72(2H, d, J=8.8 Hz), 8.21(1H, s),8.22(2H, d, J=8.8 Hz). MS (TSP): 497(M⁺+H).

b) Sodium(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d) except that 224 mg of4-nitrobenzyl(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateand 224 mg of 10% palladium on carbon were used, and that purificationwas carried out on HP-20 (20% methanol in water) and on COSMOSEAL40C18-PREP (10% methanol in water), the title compound was obtained in ayield of 103 mg.

NMR (D₂O) δ (HOD=4.80 ppm): 1.24(3H, d, J=6.9 Hz), 1.31(3H, d, J=6.6Hz), 2.28(3H, s), 2.65(3H, s), 3.50-3.65(2H, m), 4.24-4.35(2H, m),7.79(1H, s). MS (TSP): 384 (M⁺+Na), 362 (M⁺+H).

Example 90 Sodium (1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl (1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 0.46 g from 0.36 g of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 0.47 g of7-formylaminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.27(3H, d, J=7.4 Hz), 1.38(3H, d, J=6.3 Hz), 3.34(1H,dd, J=2.8, 6.6 Hz), 3.45(1H, m), 4.25(1H, m), 4.45(1H, dd, J=2.8, 9.4Hz), 4.49(2H, s), 5.29(1H, d, J=13.5 Hz), 5.50(1H, d, J=13.5 Hz),7.66(2H, d, J=8.5 Hz), 8.00(1H, s), 8, 19(1H, s), 8.22(2H, d, J=8.5 Hz),8.30(1H, s).

b) Sodium (1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d), the title compound was obtainedin a yield of 58 mg from 0.27 g of 4-nitrobenzyl(1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazole2-yl)-6-((1R-)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=7.1 Hz), 1.31((3H, d, J=6.3Hz), 3.45-3.60(2H, m), 4.20-4.30(2H, m), 4.43(2H, s), 7.84(1H, s),8.05(1H, s), 8.16(1H, s).

Example 91 Acetoxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

To a solution-of 60.2 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatein 1.4 ml of DMF was added 67.7 mg of acetoxymethyl bromide under theatmosphere of argon at a temperature of −30° C., and the mixture wasstirred for 3 hours during which the temperature was raised up to −10°C. The reaction mixture was diluted twice with 20 ml of ethy acetate,and washed twice with 10 ml of semi-saturated aqueous saline. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to a volume of 2 ml. The residuethus obtained was purified by column chromatography on silica gel(dichloromethane:methanol=15:1) and Sephadex LH-20(dichloromethane:methanol=1:1) in this sequence to give 22.1 mg of thetitle compound.

NMR (CDCl₃) δ: 1.39(3H, d, J=6.3 Hz), 2.10(3H, s), 3.32-3.40(3H, m),4.25-4.34(1H, m), 4.37-4.45(1H, m), 5.78(1H, d, J=5.6 Hz), 5.86(1H, d,J=5.6 Hz), 7.13(2H, s), 7.79(1H, s). MS (TSP): 392 (M⁺+H).

Example 92 1-(acetoxy)ethyl(5R,6S)-2-(imidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 91, the title compound was obtained ina yield of 21.2 mg from 56.4 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 70.6 mg of 1-(acetoxy)ethyl iodide.

NMR (CDCl₃) δ: 1.35-1.48(6H, m), 2.05-2.10(3H, m), 3.30-3.41(3H, m),4.23-4.32(1H, m), 4.36-4.45(1H, m), 6.85-6.92(1H, m), 7.08, 7.10(total1H, s each), 7.12(1H, s), 7.83, 7.84(total 1H, s each). MS (TSP): 406(M⁺+H).

Example 93 (1-methylcyclohexan-1-yl)carbonyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 91, the title compound was obtained ina yield of 55.5 mg from 62.5 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 69.8 mg of (1-methylcyclohexan-1-yl)carbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.15-1.25(6H, m), 1.36(3H, s), 1.37(3H, d, J=6.3 Hz),1.40-1.56(3H, m), 1.93-2.06(2H, m), 3.31-3.29(3H, m), 4.25-4.33(1H, m),4.37-4.45(1H, m), 5.82(1H, d, J=5.5 Hz), 5.87(1H, d, J=5.5 Hz), 7.12(1H,s), 7.14(1H, s), 7.82(1H, s). MS (TSP): 474 (M⁺+H).

Example 94 1-(ethoxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 91, the title compound was obtained ina yield of 28.4 mg from 60.0 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 85.9 mg of 1-(ethoxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.21-1.36(6H, m), 1.40-1.46(3H, m), 3.24-3.32(3H, m),4.12-4.28(3H, m), 4.30-4.39(1H, m), 6.71-6.47(1H, m), 7.05(2H, s),7.75(1H, s). MS (TSP): 436 (M⁺+H).

Example 95 1-(isopropoxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

To a solution of 48 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatein 1 ml of DMF was added 73 mg of 1-(isopropoxycarbonyloxy)ethyl iodideunder the atmosphere of argon at −20° C., and the mixture was stirredfor 3 hours during which the temperature was raised up to −10° C. Thereaction mixture was extracted twice with 20 ml of ethyl acetate, andwashed twice with 10 ml of semi-saturated aqueous saline. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to a volume of 2 ml. The residuethus obtained was purified by column chromatography on silica gel(chloroform:methanol=9:1) and on Sephadex LH-20(dichloromethane:methanol=1:1) in this sequence to give the titlecompound in a yield of 22 mg.

NMR (CDCl₃) δ: 1.28-1.47(12 Hz, m), 3.24-3.42(3H, m), 4.21-4.47(2H, m),6.67-6.88(1H, m). 7.10(1H, s), 7.13(1H, s), 7.85(1H, s). MS (TSP): 450(M⁺+H).

Example 96 1-(cyclohexyloxycarbonyloxy)ethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 95, the title compound was obtained ina yield of 45 mg from 48 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 63 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.

NMR (CDCl₃) δ: 1.20-1.67(12H, m), 1.68-1.84(2H, m), 1.86-2.20(2H, m),3.24-3.45(3H, m), 4.22-4.48(2H, m), 4.57-4.71(1H, m), 6.77-6.88(1H, m),7.11, 7.12(total 1H, s each), 7.14(1H, s), 7.84, 7.85(total 1H, s each).MS (TSP): 490 (M⁺+H).

Example 97 Cyclohexyloxycarbonyloxy methyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 91, the title compound was obtained ina yield of 39.5 mg from 61.7 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 69.8 mg of cyclohexyloxycarbonyloxymethyl iodide.

NMR (CDCl₃) δ: 1.23-1.98(10H, m), 1.38(3H, d, J=6.2 Hz), 3.33-3.42(3H,m), 4.26-4.36(1H, m), 4.36-4.46(1H, m), 4.00-4.70(1H, m), 5.80(1H, d,J=5.7 Hz), 5.88(1H, d, J=5.7 Hz), 7.13(1H, s), 7.18(1H, s), 7.83(1H, s).MS (TSP): 476 (M⁺+H).

Example 98 3-phthalidyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate(diastereomer mixture)

In the same manner as in Example 95, the title compound was obtained ina yield of 24 mg from 42 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 39 mg of 3-phthalidyl bromide.

NMR (CDCl₃) δ: 1.36, 1.37(total 3H, d each, J=6.3 Hz), 3.13-3.45(3H, m),4.21-4.50(2H, m), 6.98, 6.99(total 1H, s each), 7.10, 7.25(total 1H, seach), 7.40(1H, s), 7.80, 7.87(total 1H, s each), 7.35-7.91(4H, m). MS(TSP): 452 (M⁺+H).

Example 99 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 91, the title compound was obtained ina yield of 15.9 mg from 65.3 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylateand 65.8 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide.

NMR (CDCl₃) δ: 1.39(3H, d, J=6.3 Hz), 2.78(3H, s), 3.35-3.40(3H, m),4.29-4.34(1H, m), 4.38-4.46(1H, m), 4.90(1H, s), 4.91(1H, s), 7.03(1H,s), 7.12(1H, s), 7.73(1H, s). MS (TSP): 476 (M⁺+H).

Example 100 Pivaloyloxymethyl (1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 33 mg of sodium (1S,5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.8 ml of DMF was added 29 mg of pivaloyloxymethyl iodide at −30° C.,and the mixture was stirred for 1 hour during which the temperature wasraised up to room temperature. The reaction mixture was diluted with 30ml of dichloromethane, washed with semi-saturated aqueous saline, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue thus obtained was purified by columnchromatography on silica gel (ethyl acetate:methanol=4:1) to give thetitle compound in a yield of 29 mg.

NMR (CDCl₃) δ: 1.20(9H, s), 1.24(3H, d, J=7.2 Hz), 1.34(3H, d, J=6.2Hz), 3.31(1H, dd, J=2.8, 6.5 Hz), 3.41(1H, m), 3.49(2H, s),4.25-4.35(2H, m), 4.45-4.60(2H, m), 5.86(1H, d, J=5.6 Hz), 5.98(1H, d,J=5.6 Hz), 6.72(1H, br.s s), 8.00(1H, s), 8.26(1H, s), 8.34(1H, s).

Example 101 Sodium (5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl (5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 0.70 g from 0.42 g of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and0.47 g of7-formylaminomethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d₆) δ: 1.17(3H, d, J=6.0 Hz), 3.15-3.30(2H, m), 3.50-3.62(1H,m), 3.95-4.05(1H, m), 4.25-4.33(3H, m), 5.28(1H, d, J=13.5 Hz), 5.33(1H,d, J=13.5 Hz), 7.37(1H, s), 7.52(2H, d, J=8.3 Hz), 7.96(1H, s), 8.14(1H,s), 8.17(2H, d, J=8.3 Hz).

b) Sodium (5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d), the title compound was obtainedin a yield of 27 mg from 0.55 g of 4-nitrobenzyl(5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.3 Hz), 3.20(1H, dd, J=2.9,5.9 Hz), 3.40-3.48(1H, m), 3.58(1H, dd, J=2.9, 5.9 Hz), 4.23-4.30(1H,m), 4.32-4.41(1H, m), 4.50(2H, s), 7.05(1H, s), 7.94(1H, s), 8.17(1H,s).

Example 102 Pivaloyloxymethyl(5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 50, the title compound was obtained ina yield of 24 mg from 45 mg of sodium(5R,6S)-2-(7-formylaminomethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.20(9H, s), 1.35(3H, d, J=6.2 Hz),3.29-3.40(3H, m), 4.22-4.32(1H, m), 4.35-4.44(1H, m), 4.50(2H, d, J=5.6Hz), 5.73(1H, d, J=5.6 Hz), 5.83(1H, d, J=5.6 Hz), 6.85(1H, t, J=5.6Hz), 7.06(1H, s), 7.72(1H, s), 8.22(1H, s).

Example 103(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 124 mg of 4-nitrobenzyl(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained from 255 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and401 mg of 7-carbamoyl-3-(-tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.41(3H, d, J=6.1 Hz), 3.39(3H, m), 4.32(1H, m), 4.46(1H,m), 5.21(1H, d, J=13.0 Hz), 5.37(1H, d, J=13.0 Hz), 7.17(1H, s),7.47(2H, d, J=8.7 Hz), 7.56(1H, s), 8.19(2H, d, J=8.7 Hz).

b)(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 42.3 mg from 124 mg of 4-nitrobenzyl(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.33(3H, d, J=6.5 Hz), 3.23(1H, dd, J₁=17.0Hz, J₂=9.9 Hz), 3.48(1H, dd, J₁=17.0 Hz, J₂=8.5 Hz), 3.60(1H, m),4.29(1H, m), 4.40(1H, m), 7.21(1H, s), 7.87(1H, s).

Example 104 Pivaloyloxymethyl(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 14.1 mg from 44.6 mg of(5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.19(9H, s), 1.37(3H, d, J=6.3 Hz), 3.38(3H, m), 4.29(1H,m), 4.43(1H, m), 5.71(1H, br.s), 5.77(1H, d, J=5.5 Hz), 5.88(1H, d,J=5.5 Hz), 6.91(1H, br.s), 7.21(1H, s), 7.71(1H, s).

Example 105(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 121.3 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylatewas obtained as a yellowish orange powder from 99.3 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateand 1.0 ml of methyl iodide.

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.3 Hz), 1.23(3H, d, J=7.2 Hz), 2.44(3H,s), 2.83(3H, s), 3.48(1H, dd, J₁=5.9 Hz, J₂=2.9 Hz), 3.73-3.84(1H, m),3.80(3H, s), 4.02-4.09(1H, m), 4.39(1H, dd, J₁=10.1 Hz, J₂=2.9 Hz),5.19(1H, d, J=5.2 Hz), 5.40(1H, d, J=13.8 Hz), 5.52(1H, d, J=13.8 Hz),7.73(2H, d, J=8.8 Hz), 8.24(2H, d, J=8.8 Hz), 8.59(1H, s). MS (TSP): 511(M⁺).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5,6,7-trimethylimidazo[5,1-b]-thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b) except that 115 mg of4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateiodide was used and that purification was carried out on CHP-20P (20-30%methanol in water) and on COSMOSEAL 40C18-PREP (20% methanol in water),the title compound was obtained in a yield of 9.1 mg as a milk-whiteflocculate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.26(3H, d, J=7.1 Hz), i.31(3H, d, J=6.5Hz), 2.39(3H, s), 2.76(3H, s), 3.55(1H, dd, J₁=6.2 Hz, J₂=2.8 Hz),3.57-3.67(1H, m), 3.79(3H, s), 4.28(1H, quintet, J=6.2 Hz), 4.34(1H, dd,J₁=9.3 Hz, J₂=2.8 Hz), 7.92(1H, s). MS (TSP): 376 (M⁺+H).

Example 106 Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 1.53 g from 994.3 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and1.76 g of7-t-butyldimethylsilyloxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 0.14(6H, s), 0.96(9H, s), 1.37(3H, d, J=6.3 Hz), 2.48(1H,br.s, s), 3.33-3.40(3H, m), 4.26-4.33(1H, m), 4.39-4.47(1H, m), 4.83(2H,s), 5.19(1H, d, J=13.5 Hz), 5.33(1H, d, J=13.5 Hz), 7.02(1H, s),7.39(2H, d, J=8.9 Hz), 7.74(1H, s), 8.14(2H, d, J=8.9 Hz). MS (TSP): 599(M⁺).

b) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

To a solution of 848.8 mg of 848.8 mg of 4-nitrobenzyl(5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatein 20 ml of THF was added 1.22 ml of acetic acid and 7.1 ml of a 1 Msolution of tetra-n-butylammonium fluoride in THF, and the mixture wasstirred at room temperature for 2.5 hours. After neutralizing themixture with a saturated aqueous sodium hydrogen carbonate solution, itwas extracted two times with ethyl acetate, washed with semi-saturatedaqueous saline, and dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on silica gel (ethylacetate:methanol=9:1) to give 324.3 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.29(3H, d, J=6.3 Hz), 3.40-3.48(31H, m), 4.18-4.28(1H,m), 4.32-4.40(1H, m), 4.15(2H, s), 5.13(2H, d, J=13.9 Hz), 5.28(2H, d,J=13.9 Hz), 6.98(1H, s), 7.35(2H, d, J=8.7 Hz), 7.12(1H, s), 8.10(2H, d,J=8.7 Hz). MS (TSP): 485 (M⁺+H).

c) Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d ), the title compound wasobtained in a yield of 57.7 mg from 157.0 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.4 Hz), 3.10-3.27(1H, m),3.41-3.50(1H, m), 3.57-3.61(1H, m), 4.20-4.40(2H, m), 4.76(2H, s),7.23(1H, s), 8.26(1H, s).

Example 107 Sodium(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 183.0 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 15 ml of dichloromethane 15 ml was added 596.7 mg of manganesedioxide, and the mixture was stirred at room temperature for 38 hours.The catalyst was removed by filtration on Celite, and the filtrate wasremoved under reduced pressure. The residue thus obtained was purifiedby column chromatography on silica gel (ethyl acetate:methanol=9:1) togive 127 mg of 127 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.24(3H, d, J=7.2 Hz), 1.32(3H, d, J=6.3 Hz), 3.34(1H,dd, J₁=6.4 Hz, J₂=2.7 Hz), 3.41-4.50(1H, m), 4.21-4.32(1H, m), 4.37(1H,dd, J₁=9.6 Hz, J₂=2.7 Hz), 5.20(1H, d, J=13.7 Hz), 5.45(1H, d, J=13.7Hz), 7.59(2H, d, J=8.4 Hz), 8.02(1H, s), 8.14(2H, d, J=8.4 Hz), 8.42(1H,s), 9.83(1H, s).

b) Sodium(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d), the title compound was obtainedin a yield of 56.7 mg from 127.0 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.19(3H, d, J=6.6 Hz), 1.32(3H, d, J=5.9Hz), 3.46-3.60(2H, m), 4.21-4.34(2H, m), 7.94(1H, s), 8.12(1H, s),9.41(1H, s).

Example 108 Pivaloyloxymethyl(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135, the title compound was obtained ina yield of 26.0 mg from 31.4 mg of sodium(1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.19(9H, s), 1.33(3H, d, J=7.2 Hz), 1.36(3H, d, J=6.3Hz), 3.35-3.40(1H, m), 3.49-3.56(1H, m), 4.23-4.27(1H, m), 4.41(1H, dd,J₁=9.2 Hz, J₂=2.8 Hz), 5.87(1H, d, J=5.7 Hz), 5.99(1H, d, J=5.7 Hz),8.11(1H, s), 8.51(1H, s), 9.91(1H, s).

Example 109(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-thyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 109 mg from 215 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 324 mg of 7-carbamoyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.4 Hz), 1.40(3H, d, J=6.3 Hz), 3.38(1H,dd, J₁=6.6 Hz, J₂=2.8 Hz), 3.50(1H, m), 4.32(1H, m), 4.41(1H, dd, J₁=9.7Hz, J₂=2.8 Hz), 5.27(1H, d, J=13.5 Hz), 5.52(1H, d, J=13.5 Hz), 5.53(1H,br.s), 6.78(1H, br.s), 7.67(2H, d, J=8.9 Hz), 7.95(1H, s), 8.24(2H, d,J=8.9 Hz), 8.50(1H, s).

b)(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b) , the title compound was obtainedin a yield of 73.8 mg from 123 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=7.1 Hz), 1.33(3H, d, J=6.4Hz), 3.53(2H, m), 4.30(2H, m), 7.92(1H, s), 8.05(1H, s).

Example 110 Pivaloyloxymethyl(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-inethyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 31.5 mg from 35.2 mg of(1S,5R,6S)-2-(7-carbamoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.20(9H, s), 1.28(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.2Hz), 3.35(1H, dd, J₁=6.8 Hz, J₂=2.7 Hz), 3.50(1H, m), 4.28(1H, m),4.41(1H, dd, J₁=9.9 Hz, J₂=2.7 Hz), 5.58(1H, br.s), 5.87(1H, d, J=5.6Hz), 5.98(1H, d, J=5.6 Hz), 6.92(1H, br.s), 8.01(1H, s), 8.51(1H, s).

Example 111 Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-carbapen-2-em-3-carboxylatewas obtained in a yield of 550 mg from 730 mg of(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.010 g of7-methoxymethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.28(3H, d, J=7.3 Hz), 1.37(3H, d, J=6.1 Hz), 3.35(3H,s), 3.3-3.5(1H, m), 3.55(1H, m), 4.27(1H, m), 4.37(1H, dd, J₁=9.5 Hz,J₂=2.3 Hz), 4.60(2H, s),5.27(1H, d, J=13.7 Hz), 5.50(1H, d, J=13.7 Hz),7.65(2H, d, J=8.7 Hz), 8.18(1H, m), 8.20(2H, d, J=8.7 Hz), 8.30(1H, s).

b) Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 550 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyniethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carlboxylatein 30 ml of THF and 30 ml of a 1/15 M phosphate buffer (pH 6.8) wasadded 660 mg of 10% Pd-C, and the mixture was stirred under theatmosphere of hydrogen at room temperature for 1 hour. After filtrationthrough Celite, the catalyst was washed with a mixture of THF:water(1:1). The combined filtrates were adjusted to pH 6.7 with a saturatedaqueous sodium hydrogen carbonate solution, washed with 30 ml of ethylacetate, and concentrated under reduced pressure. The residue thusobtained was purified by column chromatography on DIAION HP-20, andlyophilized to give 220 mg of a powder product. A 120 mg portion of theproduct was purified by column chromatography on COSMOSEAL 40C18-PREP togive the title compound in a yield of 58 mg.

NMR (D₂O) δ (HOD=4.80 ppm) 1.22(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.3 Hz),3.36(3H, s), 3.50(1H, dd, J₁=6.1 Hz, J₂=2.6 Hz), 3.54(1H, m), 4.26(1H,m), 4.29(1H, dd, J₁=9.3 Hz, J₂=2.5 Hz), 4.49(2H, s), 7.84(1H, s),8.13(1H, s).

Example 112 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 40 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.6 ml of DMF was added 4.2 mg of sodium hydrogen carbonate, and themixture was cooled to −30° C. under the atmosphere of argon.Pivaloyloxymethyl iodide (34 mg) was added, and the mixture was stirredfor 1 hour, diluted with 30 ml of ethyl acetate, and washed with 20 mlof saturated aqueous saline and 20 ml of semi-saturated squeous saline.The organic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to a volume of about 1 ml. Theconcentrate was purified by column chromatography on silica gel(chloroform:methanol=95:5) to give the title compound was obtained in ayield of 18.4 mg.

NMR (CDCl₃) δ: 1.21(9H, s), 1.28(3H, d, J=7.2 Hz), 1.36(3H, d, J=6.3Hz), 3.32(1H, dd, J₁=6.8 Hz, J₂=2.8 Hz), 3.44(3H, s), 3.4-3.5(1H, m),4.27(1H, m), 4.34(1H, dd, J₁=9.7 Hz, J₂=2.8 Hz), 4.58(2H, s), 5.88(1H,d, J=5.7 Hz), 5.93(1H, d, J=5.7 Hz), 8.02(1H, s), 8.33(1H, s).

Example 113 Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyinethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyimethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 450 mg from 697 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and896 mg of 7-methoxymethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

b) Sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-3-yl)-carbapen-2-em-3-carboxylate

In the same manner as in Example 134-d), the title compound was obtainedin a yield of 30 mg from 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-3-yl)-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(3H, d, J=6.3 Hz), 3.33(2H, m), 3.39(3H,s), 3.59(1H, dd, J₁=5.8 Hz, J₂=2.3 Hz), 4.2-4.4(2H, m), 4.60(2H, s),7.13(1H, s), 8.04(1H, s).

Example 114 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]-thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135, the title compound was obtained ina yield of 10 mg from 28 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.19(9H, s), 1.37(3H, d, J=6.3 Hz), 3.3-3.4(2H, m),3.43(3H, s), 4.27(1H, s), 4.40(1H, m), 5.78(1H, d, J=5.5 Hz), 5.88(1H,d, J=5.5 Hz), 7.14(1H, s), 7.78(1H, s).

Example 115 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 135, the title compound was obtained ina yield of 9.0 mg from 39.5 mg of sodium(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.20(3H, d, J=5.8 Hz), 3.68-3.80(3H, m), 4.90-5.05(2H,m), 5.72(1H, d, J=6.0 Hz), 5.88(1H, d, J=6.0 Hz), 6.30-6.42(2H, m),7.70(1H, s), 9.60(1H, s).

Example 116(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 253 mg from 362 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 526 mg of 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.32(3H, d, J=7.2 Hz), 1.40(3H, d, J=6.3 Hz), 3.49(1H,dd, J₁=6.4 Hz, J₂=2.8 Hz), 3.50(1H, m), 4.32(1H, m), 4.42(1H, dd, J₁=9.8Hz, J₂=2.8 Hz), 5.29(1H, d, J=13.7 Hz), 5.53(1H, d, J=13.7 Hz), 7.68(2H,d, J=8.9 Hz), 8.01(1H, s), 8.25(2H, d, J=8.9 Hz), 8.37(1H, s).

b)(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 62.1 mg from 4-nitrobenzyl(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.23(3H, d, J=7.1 Hz), 1.32(3H, d, J=6.2Hz), 3.51(1H, m), 3.59(1H, m), 4.29(2H, m), 8.00(1H, s), 8.16(1H, s).

Example 117 Pivaloyloxymethyl(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 34.3 mg from 36.7 mg of(1S,5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.21(9H, s), 1.30(3H, d, J=7.2 Hz), 1.37(3H, d, J=6.3Hz), 3.37(1H, dd, J₁=6.5 Hz, J₂=3.0 Hz), .3.50(1H, m), 4.30(1H, m),4.41(1H, dd, J₁=9.9 Hz, J₂=3.0 Hz), 5.87(1H, d, J=5.6 Hz), 5.99(1H, d,J=5.6 Hz), 8.06(1H, s), 8.37(1H, s).

Example 118(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein a yield of 258 mg was obtained from 362 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 529 mg of 7-ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.32(6H, m), 1.40(3H, d, J=6.2 Hz), 2.75(2H, q, J=7.6Hz), 3.36(1H, dd, J₁=6.5 Hz, J₂=2.8 Hz), 3.46(1H, m), 4.33(2H, m),5.28(1H, d, J=13.7 Hz), 5.52(1H, d, J=13.7 Hz), 7.68(2H, d, J=8.6 Hz),7.94(1H, s), 8.24(2H, d, J=8.6 Hz), 8.26(1H, s).

b)(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b) except that purification wascarried out by column chromatography on DIAION HP-20 (10% methanol inwater-40% methanol in water) and on COSMOSEAL 4OC18PREP(water:methanol=5:1), the title compound was obtained in a yield of 31.7mg from 164 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(9H, m), 2.82(2H, q, J=7.7 Hz), 3.56(1H,dd, J₁=6.0 Hz, J₂=3.0 Hz), 3.61(1H, m), 4.28(1H, m), 4.34(1H, dd, J₁=9.4Hz, J₂=3.0 Hz), 8.02(1H, s), 8.86(1H, s).

Example 119 Pivaloyloxymethyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 15.8 mg from 45.3 mg of(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.21(9H, s), 1.29(3H, d, J=7.2 Hz), 1.32(3H, t, J=7.6Hz), 1.37(3H, d, J=6.2 Hz), 2.75(2H, q, J=7.6 Hz), 3.32(1H, dd, J₁=6.0Hz, J₂=2.8 Hz), 3.44(1H, m), 4.31(2H, m), 5.88(1H, d, J=5.6 Hz),5.98(1H, d, J=5.6 Hz), 7.97(1H, s), 8.26(1H, s).

Example 120(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 27.8 mg from 239 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and376 mg of 5-carbamoyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CD₃OD) δ: 1.31(3H, d, J=6.3 Hz), 3.1-3.7(3H, m), 4.1-4.4(2H, m),4.9-5.2(2H, m), 7.30(2H, m), 8.1(2H, m).

b)(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 16.9 mg from 33.2 mg of 4-nitrobenzyl(5R,6S)-2-(5-carbamoylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.33(3H, d, J=6.3 Hz), 3.15(1H, dd, J₁=17.6Hz, J₂=9.9 Hz), 3.27(1H, dd, J₁=17.7 Hz, J₂=8.5 Hz), 3.53(1H, m),4.30(2H, m), 7.19(1H, s), 7.21(1H,

Example 121(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 203 mg from 348 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and529 mg of 7-ethyl-2-(-tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.31(3H, t, J=7.5 Hz), 1.39(3H, d, J=6.3 Hz), 2.74(2H, q,J=7.5 Hz), 3.32(3H, m), 4.32(2H, m), 5.30(1H, d, J=13.7 Hz), 5.54(1H, d,J=13.7 Hz), 7.68(2H, d, J=8.4 Hz), 7.93(1H, s), 8.15(1H, s), 8.23(2H, d,J=8.4 Hz).

b)(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 49.1 mg from 203 mg of 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(6H, m), 2.76(2H, q, J=7.5 Hz), 3.31(2H,m), 3.54(1H, m), 4.28(2H, m), 7.79(1H, s), 8.58(1H, s).

Example 122 Pivaloyloxymethyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 23.3 mg from 43.0 mg of(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.23(9H, s), 1.32(3H, t, J=7.6 Hz), 1.36(3H, d, J=6.3Hz), 2.74(2H, q, J=7.6 Hz), 3.29(3H, m), 4.28(2H, m), 5.91(1H, d, J=5.6Hz), 6.00(1H, d, J=5.6 Hz), 7.96(1H, s), 8.20(1H, s).

Example 123(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), the title compound was obtainedin a yield of 765 mg from 627 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and882 mg of 7-ethyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.30(3H, t), 1.38(3H, d), 2.72(2H, q), 3.25-3.45(3H, m),4.32(1H, m), 4.33(1H, m), 5.28(2H, ABq), 7.00(1H, s), 7.42(2H, d),7.67(1H, s), 8.17(2H, d).

b)(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 86.6 mg from 203 mg of 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(6H, m), 2.80(2H, q, J=7.7 Hz), 3.21(1H,dd, J₁=17.3 Hz, J₂=10.1 Hz), 3.45(1H, dd, J₁=17.3 Hz, J₂=8.9 Hz),3.59(1H, m), 4.29(1H, m), 4.38(1H, m), 7.25(1H, s), 8.33(1H, s).

Example 124 Pivaloyloxymethyl(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 29.1 mg from 41.6 mg of(5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.19(9H, s), 1.32(3H, t, J=7.6 Hz), 1.37(3H, d, J=6.3Hz), 2.75(2H, q, J=7.6 Hz), 3.35(3H, m), 4.28(1H, m), 4.40(1H, m),5.78(1H, d, J=5.5 Hz), 5.88(1H, d, J=5.5 Hz), 7.08(1H, s), 7.72(1H, s).

Example 125(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 200 mg from 276 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and417 mg of 7-cyano-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR(DMSO-d₆) δ: 1.17(3H, d, J=6.3 Hz), 3.47(2H, m), 3.54(1H, dd, J₁=6.0Hz, J₂=3.0 Hz), 4.01(1H, m), 4.27(1H, m), 5.17(1H, d, J=5.0 Hz),5.43(1H, d, J=13.7 Hz), 5.56(1H, d, J=13.7 Hz), 7.76(2H, d, J=8.5 Hz),8.25(2H, d, J=8.5 Hz), 8.43(1H, s), 8.51(1H, s).

b)(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 53.8 mg from 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.31(3H, d, J=6.4 Hz), 3.27(3H, m), 3.51(1H,dd, J₁=5.8 Hz, J₂=2.8 Hz), 4.26(2H, m), 7.82(1H, s), 8.13(1H, s).

Example 126 Pivaloyloxymethyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 18.5 mg from 41.2 mg of(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.23(9H, s), 1.37(3H, d, J=6.3 Hz), 3.34(3H, m), 4.32(2H,m), 5.90(1H, d, J=5.6 Hz), 6.02(1H, d, J=5.6 Hz), 8.03(1H, s), 8.29(1H,s).

Example 127(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide was obtained from 97.7 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-ethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

NMR (DMSO-d₆) δ: 1.18(3H, d, J=6.3 Hz), 1.22(3H, d, J=7.4 Hz), 1.29(3H,t, J=7.6 Hz), 2.88(2H, t, J=7.6 Hz), 3.49(1H, dd, J₁=5.7 Hz, J₂=3.1 Hz),3.73(1H, m), 3.98(3H, s), 4.04(1H, m), 4.39(1H, dd, J₁=10.1 Hz), J₂=3.1Hz), 5.18(1H, d, J=4.4 Hz), 5.40(1H, d, J=13.9 Hz), 5.53(1H, d, J=13.9Hz), 7.73(2H, d, J=8.7 Hz), 8.23(2H, d, J=8.7 Hz), 8.61(1H, s), 9.51(1H,s).

b)(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), the title compound was obtainedin a yield of 50.6 mg from the whole amount of 4-nitrobenzyl(1S,5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateiodide obtained above.

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=6.9 Hz), 1.33(6H, m), 2.82(2H,q, J=7.4 Hz), 3.55(2H, m), 3.94(3H, s), 4.27(2H, m), 8.02(1H, s),9.05(1H, s).

Example 128(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained from 560 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and852 mg of 5,7-dimethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (DMSO-d6) δ: 1.17(3H, d, J=6.3 Hz), 2.14(3H, s), 2.46(3H, s),3.3-3.5(3H, m), 4.01(1H, m), 4.24(1H, m), 5.16(1H, d, J=5.0 Hz),5.40(1H, d, J=14.0 Hz), 5.52(1H, d, J=14.0 Hz), 7.75(2H, d, J=8.3 Hz),8.15(1H, s), 8.24(2H, d, J=8.3 Hz).

b)(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 105.2 mg from 269 mg of 4-nitrobenzyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.2 Hz), 2.33(3H, s), 2.70(3H,s), 3.30(2H, m), 3.55(1H, m), 4.30(2H, m), 7.71(1H, s).

Example 129 Pivaloyloxymethyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 40.3 mg from 99.4 mg of(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.23(9H, s), 1.37(3H, d, J=6.3 Hz), 2.28(3H, s), 2.57(3H,s), 3.28(3H, m), 4.27(2H, m), 5.90(1H, d, J=5.6 Hz), 6.01(1H, d, J=5.6Hz), 8.02(1H, s).

Example 130(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

To a solution 428 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylatein 30 ml of dichloromethane was added 1.03 g of manganese dioxide, andthe mixture was stirred at room temperature for 18 hours. The catalystwas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue thus obtained was washed with diethylether to give 202.8 mg of 4-nitrobenzyl(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (CDCl₃) δ: 1.32(3H, d, J=6.4 Hz), 3.30-3.40(4H, m), 4.21-4.36(1H,m), 4.42(1H, dt, J₁=9.6 Hz, J₂=3.0 Hz), 5.14(1H, d, J=13.5 Hz), 5.29(1H,d, J=13.5 Hz), 7.40(2H, d, J=8.8 Hz), 7.72(1H, s), 8.09(2H, d, J=8.8Hz), 9.79(1H, s). MS (TSP): 483 (M⁺+H).

b)(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 45.1 mg from 142.1 mg of 4-nitrobenzyl(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.27(3H, d, J=6.2 Hz), 3.19-3.28(1H, m),3.43-3.53(1H, m), 3.59-3.62(1H, m), 4.25-4.32(1H, m), 4.36-4.44(1H, m),7.34(1H, s), 7.99(1H, s), 9.58(1H, s).

Example 131 Pivaloyloxymethyl(5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 8.2 mg from 31.4 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylicacid and 0.016 mg of pivaloyloxymethyl iodide.

NMR (CDCl₃) δ: 1.19(9H, s), 1.38(3H, d, J=6.3 Hz), 2.33(1H, br.s, s),3.37-3.41(3H, m), 4.28-4.34(1H, m), 4.42-4.50(1H, m), 5.77(1H, d, J=5.5Hz), 5.88(1H, d, J=5.5 Hz), 7.27(1H, s), 7.84(1H, s).

Example 132(5R,6S)-2-(7-ethyl-6-methylimidazo[5,1-b]-thiazolium-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 14, the title compound was obtained ina yield of 2.2 mg from 73.9 mg of 4-nitrobenzyl(5R,6S)-2-(7-ethylimidazo[5,1-b]-thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.4 Hz), 1.40(3H, t, J=7.4Hz), 2.90(2H, q, J=7.4 Hz), 3.24(1H, dd, J₁=17.1 Hz, J₂=9.8 Hz),3.45(1H, dd, J₁=17.1 Hz, J₂=8.7 Hz), 3.60(1H, m), 3.96(3H, s), 4.29(1H,m), 4.39(1H, m), 7.44(1H, s), 8.84(1H, s).

Example 133(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateIodide

In the same manner as in Example 4-a) except that the reaction wascarried out for 4 days, 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylateiodide was obtained from 86.1 mg of 4-nitrobenzyl(5R,6S)-2-(5,7-dimethylimidazo[5,1-b]-thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylateiodide.

NMR(DMSO-d₆) δ: 1.17(3H, d, J=6.5 Hz), 2.44(3H, s), 2.84(3H, s),3.50(2H, m), 3.60(1H, m), 3.80(3H, s), 4.04(1H, m), 4.33(1H, m),5.20(1H, br.s), 5.44(1H, d, J=13.6 Hz), 5.56(1H, d, J=13.6 Hz), 7.76(2H,d, J=8.4 Hz), 8.26(2H, d, J=8.4 Hz), 8.55(1H, s).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-trimethylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate(inner salt)

In the same manner as in Example 4-b), the title compound was obtainedin a yield of 19.8 mg from the whole amount of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5,6,7-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate.NMR (D₂O) δ (HOD=4.80 ppm): 1.28(3H, d, J=6.4 Hz), 2.34(3H, s), 2.73(3H,s), 3.25(2H, m), 3.46(1H, m), 3.76(3H, s), 4.22(2H, m), 7.73(1H, s).

Example 134 Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

a) 4-nitrobenzyl(1S,5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(Diastereoisomer mixture of about 1:1)

In the same manner as in Example 5-a), 4-nitrobenzy(1S,5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1) was obtained in a yield of 332 mgfrom 575 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 1.09 g of7-(1-t-butyldimethylsilyloxy)ethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole(racemicmixture).

NMR (CDCl₃) δ: 0.09(1.5H, s), 0.11(1.5H, s), 0.13(3H, s), 0.95(4.5H, s),0.96(4.5H, s), 1.30(3H, d, J=7.2 Hz), 1.39(3H, d, J=6.3 Hz), 1.50(3H,m), 3.36(1H, dd, J₁=6.5 Hz, J₂=2.7 Hz), 3.45(1H, m), 4.34(2H, m),5.09(1H, m), 5.26(1H, d, J=13.7 Hz), 5.51(1H, d, J=13.7 Hz), 7.67(2H, d,J=8.8 Hz), 7.93(1H, s), 8.23(2H, d, J=8.8 Hz), 8.32(0.5H, s), 8.32(0.5H,s).

b) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate(Diastereoisomer mixture of about 1:1)

To a solution of 332 mg of 4-nitrobenzyl(1S,5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1--methyl-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1) in 3 ml of DMF and 1 ml of NMPwas added 180 mg of ammonium hydrogen dif luoride, and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with 50 ml of ethyl acetate and 50 ml of aqueous saline, andadjusted to pH 8 with a sodium hydrogen carbonate solution to pH 8. Theorganic layer was separated, and the aqueous layer was further extractedwith ethyl acetate. The combined organic layer was washed twice withaqueous saline, dried over anhydrous magnesium sulfate, and the solventwas removed under reduced pressure. The residue thus obtained waspurified by column chromatography on silica gel(dichloromethane:methanol=20:1) to give 80.5 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1).

NMR (CDCl₃) δ: 1.30(3H, d, J=7.2 Hz), 1.40(3H, d, J=6.3 Hz), 1.61(3H, d,J=6.5 Hz), 3.36(1H, dd, J₁=6.3 Hz, J₂=2.6 Hz), 3.46(1H, m), 4.34(2H, m),5.07(1H, q, J=6.5 Hz), 5.27(1H, d, J=13.7 Hz), 5.52(1H, d, J=13.7 Hz),7.68(2H, d, J=8.6 Hz), 7.96(1H, s), 6.24(2H, d, J=8.6 Hz), 8.32(1H, s).

c) 4-nitrobenzyl(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 74-a), 4-nitrobenzyl(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatewas obtained from 197 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1).

NMR (CDCl₃) δ: 1.31(3H, d, J=7.4 Hz), 1.40(3H, d, J=6.2 Hz), 2.61(3H,s), 3.40(1H, dd, J₁=6.6 Hz, J₂=2.9 Hz), 3.52(1H, m), 4.32(1H, m),4.42(1H, dd, J₁=9.7 Hz, J₂=2.9 Hz), 5.27(1H, d, J=13.5 Hz), 5.52(1H, d,J=13.5 Hz), 7.67(2H, d, J=8.5 Hz), 8.01(1H, s), 8.22(2H, d, J=8.5 Hz),8.50(1H, s).

d) Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 98.2 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 5.8 ml of THF and 5.8 ml of 1/15 M sodium phosphate buffer (pH 6.6)was added 98 mg of 10% Pd-C. The reactor was purged with hydrogen, andthe reaction mixture was stirred at room temperature for 2 hours. Thecatalyst was removed by filtration through Celite, and washed withwater. The filtrate was adjusted to pH 6.5 with an aqueous sodiumhydrogen carbonate solution, washed with ethyl acetate, and the aqueouslayer was purified by column chromatography on DIAION HP-20 (20%methanol in water) to give 38.1 mg of the title compound.

NMR (D₂O) δ (HOD=4.80 ppm): 1.20(3H, d, J=7.2 Hz), 1.33(3H, d, J=6.4Hz), 2.45(3H, s), 3.50(1H, dd, J₁=6.1 Hz, J₂=2.5 Hz), 3.57(1H, m),4.28(1H, m), 4.33(1H, dd, J₁=9.3 Hz, J₂=2.5 Hz), 7.92(1H, s), 8.05(1H,s).

Example 135 Pivaloyloxymethyl(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 38.1 mg of sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 3 ml of DMF was added 0.021 ml of pivaloyloxymethyl iodide under theatmosphere of argon at −30° C., and the mixture was stirred for 1.5hours. The reaction mixture was diluted with 20 ml of ethyl acetate andwashed with 20 ml of semi-saturated aqueous saline. The organic layerwas dried over anhydrous magnesium sulfate, filtered, and concentratedunder reduced pressure to a volume of 3 ml. The residue thus obtainedwas purified by column chromatography on silica gel(dichloromethane:methanol=20:1) and on Sephadex LH-20(chloroform:methanol=1:1) in this sequence to give 35.8 mg of the titlecompound.

NMR (CDCl₃) δ: 1.20(9H, s), 1.29(311, d, J=7.3 Hz), 1.37(3H, d, J=6.3Hz), 2.62(3H, s), 3.36(1H, dd, J₁=6.5 Hz, J₂=2.9 Hz), 3.50(1H, m),4.30(1H, m), 4.40(1H, dd, J₁=9.7 Hz, J₂=2.9 Hz), 5.87(1H, d, J=5.6 Hz),5.99(1H, d, J=5.6 Hz), 8.05(1H, s), 8.51(1H, s).

Example 136(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(Diastereoisomer mixture of about 1:1)

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]-thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1) was obtained in a yield of 1.26 gfrom 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and3.00 g of7-(1-t-butyldimethylsilyloxy)ethyl-3-(-tri-n-butylstannyl)imidazo[5,1-b]thiazole(racemic mixture).

NMR (CDCl₃) δ: 0.10(3H, s), 0.13(3H, s), 0.96(9H, s), 1.39(3H, d, J=6.3Hz), 1.47(1.5H, d, J=6.2 Hz), 1.49(1.5H, d, J=6.2 Hz), 3.36(3H, m),4.31(1H, m), 4.42(1H, m), 5.08(1H, q, J=6.2 Hz), 5.23(1H, d, J=13.5 Hz),5.37(1H, d, J=13.5 Hz), 7.04(0.5H, s), 7.05(0.5H, s), 7.43(1H, d, J=8.2Hz), 7.45(1H, d, J=8.2 Hz), 7.66(1H, s), 8.18(2H, d, J=8.2 Hz).

b) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]thiazol-3-yl]-1-carbapen-2-em-3-carboxylate(Diastereoisomer mixture of about 1:1)

In the same manner as in Example 134-b) except that the reaction wascarried out for 4 days, 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]-thiazol-3-yl]-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1) was obtained in a yield of 245 mgfrom 1.03 g of 4-nitrobenzyl(5R,6S)-2-[7-(1-t-butyldimethylsilyloxy)ethylimidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1).

NMR (CDCl₃) δ: 1.41(3H, d, J=6.3 Hz), 1.59(3H, d, J=6.3 Hz), 3.36(3H,m), 4.32(1H, m), 4.43(1H, m), 5.03(1H, q, J=6.3 Hz), 5.21(1H, d, J=13.5Hz), 5.36(1H, d, J=13.5 Hz), 7.03(1H, s), 7.44(2H, d, J=8.8 Hz),7.67(1H, s), 8.18(2H, d, J=8.8 Hz).

c) 4-nitrobenzyl(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 74-a), 4-nitrobenzyl(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 58.6 mg from 262 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(1-hydroxy)ethylimidazo[5,1-b]thiazol-3-yl]-1-carbapen-2-em-3-carboxylate(diastereoisomer mixture of about 1:1).

NMR (CDCl₃) δ: 1.40(3H, d, J=6.3 Hz), 2.57(3H, s), 3.41(3H, m), 4.33(1H,m), 4.48(1H, m), 5.20(1H, d, J=13.4 Hz), 5.36(1H, d, J=13.4 Hz),7.23(1H, s), 7.46(2H, d, J=8.8 Hz), 7.79(1H, s), 8.16(2H, d, J=8.8 Hz).

d)(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 6.6 mg from 58.6 mg of 4-nitrobenzyl(5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.3 Hz), 2.56(3H, s), 3.25(1H,m), 3.48(1H, m), 3.61(1H, m), 4.29(1H, m), 4.40(1H, m), 7.31(1H, s),7.96(1H, s).

Example 137(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a high polaroxime isomer)

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a high polaroxime isomer)

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a high polaroxime isomer) was obtained in a yield of 275 mg from 362 mg of4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 564 mg of7-methoxyiminomethyl-2-(tri-n-butyls-tannyl)imidazo[5,1-b]thiazole(geometricalisomer derived from a raw material which is a high polar oxime isomer)described in Preparation 14.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.4 Hz), 1.39(3H, d, J=6.2 Hz), 3.38(1H,dd, J₁=6.3 Hz, J₂=2.8 Hz), 3.50(1H, m), 4.00(3H, s), 4.33(1H, m),4.40(1H, dd, J₁=9.6 Hz, J₂=2.8 Hz), 5.26(1H, d, J=13.7 Hz), 5.52(1H, d,J=13.7 Hz), 7.46(1H, s), 7.66(2H, d, J=8.8 Hz), 7.96(1H, s), 8.21(2H, d,J=8.8 Hz), 8.33(1H, s).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a high polaroxime isomer)

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 14.7 mg from 225 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a high polaroxime isomer).

NMR (D₂O) δ (HOD=4.80 ppm): 1.19(3H, d, J=7.0 Hz), 1.32(3H, d, J=6.5Hz), 3.47(2H, m), 3.88(3H, s), 4.28(2H, m), 7.23(1H, s), 7.80(1H, s),8.13(1H, s).

Example 138(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 201 mg from 205 mg of(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 299 mg of7-(N-methylcarbamoyl)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.30(3H, d, J=7.3 Hz), 1.40(3H, d, J=6.2 Hz), 1.72(1H,m), 3.01(3H, d, J=5.0 Hz), 3.38-3.41(1H, m), 3.45-3.54(1H, m),4.28-4.37(1H, m), 4.40-4.45(1H, m), 5.27(1H, d, J=13.7 Hz), 5.51(1H, d,J=13.7 Hz), 7.66(2H, d, J=8.9 Hz), 7.92(1H, s), 8.23(2H, d, J=8.9 Hz),8.48(1H, s). MS (APCI): 526 (M⁺+H).

b)(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 61 mg from 116.2 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=6.9 Hz), 1.31(3H, d, J=6.0Hz), 2.91(3H, s), 3.48-3.61(2H, m), 4.23-4.32(2H, m), 7.92(1H, s),8.04(1H, s).

Example 139 Pivaloyloxymethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 23.0 mg from 41.8 mg of(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylateand 0.023 ml of pivaloyloxymethyl iodide.

NMR (CDCl₃) δ: 1.17(9H, s), 1.28(3H, d, J=7.4 Hz), 1.37(3H, d, J=6.3Hz), 2.26-2.29(1H, m), 3.01(3H, d, J=5.0 Hz), 3.32-3.38(1H, m),3.45-3.54(1H, m), 4.26-4.33(1H, s), 4.38-4.41(1H, m), 5.87(1H, d, J=5.6Hz), 5.99(1H, d, J=5.6 Hz), 6.88-6.93(1H, m), 7.97(1H, s), 8.51(1H, s).MS (TSP): 505 (M⁺+H).

Example 140 Sodium(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

A solution of 725 mg of 4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylatein 6 ml of anhydrous acetonitrile was cooled to −25° C. under theatmosphere of argon. To the solution was added diisopropylethylamine(520 mg) followed by 636 mg of anhydrous trifluoromethanesulfonic acid,and the mixture was stirred for 30-40 minutes, then diluted with 50 mlof ethyl acetate and 20 ml of semi-saturated aqueous saline, stirred andseparated. The organic layer was washed with a mixture of 15 ml ofsemi-saturated aqueous saline and 2 ml of 1 N hydrochloric acid and witha mixture of 15 ml of semi-saturated aqueous saline and 1 ml of asaturated sodium hydrogen carbonate solution, stirred, dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. After concentrating the solvent to a volume of about 1 ml, itwas diluted with 6 ml of NMP, and the mixture was concentrated again. Tothe concentrate were added a solution of a mixture of7-(N,N-dimethylcarbamoyl)-2-(-tri-n-butylstannyl)imidazothiazole and7-(N,N-dimethylcarbamoyl)-3-(tri-n-butylstannyl)imidazo-thiazole (ca1:1) described in Preparation 22 in 3 ml of NMP, followed by 55 mg oftris(dibynzylideneacetone)dipalladium (0), 56 mg oftri-2-furylphosphine, and 560 mg of sufficiently desiccated zincchloride, and the mixture was stirred under the atmosphere of argon atroom temperature for 1 hour and at 55° C. for further 2 hours. Thereaction mixture was diluted with 100 ml of ethyl acetate, washed with50 ml of water and three or four times with 50 ml of semi-saturatedaqueous saline, and dried over anhydrous magnesium sulfate, and thesolvent was removed under reduced pressure. The residue thus obtainedwas purified by column chromatography on silica gel(dichloromethane:methanol=98:2-95:5) to give 699 mg of a mixture of4-nitrobenzyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylateand 4-nitrobenzyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate(ca. 1:1).

To a solution of the mixture in 28.5 ml of THF and 28.5 ml of a 1/15 Mphosphate buffer (pH 6.8) was added 600 mg of 10% Pd-C, and the reactorwas purged with hydrogen.

The reaction mixture was stirred vigorously at room temperature for 2hours and filtered through Celite, and the Celite was washed with 50 mlof a THF/water (1:1). The combined filtrate was washed with 80 ml ofethyl acetate, and the solvent was concentrated under reduced pressure.The residue thus obtained was purified by desalting by columnchromatography on DIAION HP-20 (water—water:acetonitrile=9:1), then byseparation by preparative column chromatography on COSMOSEAL 5C18-MS(20×250 mm) (acetonitrile:water=1:1), and the first fractions amongthose containing two primary components were collected, concentratedunder reduced pressure, and lyophilized to give the title compound in ayield of 156 mg.

NMR (D₂O) δ (HOD=4.80 ppm): 1.21(3H, d, J=7.1 Hz), 1.32(3H, d, J=6.3Hz), 2.9-3.7(7H, m), 3.49(1H, dd, J₁=6.3 Hz, J₂=2.5 Hz), 4.27(2H, m),7.89(1H, s), 8.01(1H, s).

Example 141 Pivaloyloxymethyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 50 mg of sodium(1R,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-carbapen-2-em-3-carboxylatein 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and themixture was cooled to −30° C. under the atmosphere of argon. Thereaction mixture was added with 43 mg of pivaloyloxymethyl iodide,stirred for 1 hour, extracted with 20 ml of ethyl acetate, and theorganic layer was washed with 12 ml of semi-saturated aqueous saline,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to a volume of about 1 ml. The residue thus obtained waspurified by column chromatography on silica gel(dichloromethane:methanol=95:5) to give 55 mg of the title compound.

NMR (CDCl₃) δ: 1.18(9H, s), 1.26(3H, d, J=7.3 Hz), 1.35(3H, d, J=6.3Hz), 3.0-3.8(6H, m), 3.32(1H, dd, J₁=7.1 Hz, J₂=2.8 Hz), 3.46(1H, m),4.23(1H, m), 4.37(1H, dd, J₁=9.8 Hz, J₂=2.8 Hz), 5.85(1H, d, J=5.6 Hz),5.96(1H, d, J=5.6 Hz), 8.00(1H, s), 8.50(1H, s).

Example 142 Sodium(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

In the preparative chromatography in Example 140, the second fractionsamong those containing two primary components were collected,concentrated under reduced pressure, and lyophilized to give the titlecompound in a yield of 154 mg.

NMR (CDCl₃) δ: 1.14(3H, d, J=7.1 Hz), 1.31(3H, d, J=6.4 Hz), 3.0-3.7(8H,m), 4.3(1H, m), 4.41(1H, dd, J₁=9.9 Hz, J₂=3.0 Hz), 7.25(1H, s),8.01(1H, s).

Example 143 Pivaloyloxymethyl(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate

To a solution of 50 mg of sodium(1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)imidazo[5,1-b]thiazol-3-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatein 0.7 ml of DMF was added 5.0 mg of sodium hydrogen carbonate, and themixture was cooled to −30° C. under the atmosphere of argon. Afteraddition of 43 mg of pivaloyloxymethyl iodide, the mixture was stirredfor 1 hour, extracted with 20 ml of ethyl acetate, and the organic layerwas washed with 12 ml of semi-saturated aqueous saline, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure toa volume of about 1 ml. The residue thus obtained was purified by columnchromatography on silica gel (dichloromethane:methanol=95:5) to give 48mg of the title compound.

NMR (CDCl₃) δ: 1.14(9H, s), 1.12(3H, d, J=7.6 Hz), 1.34(3H, d, J=6.2Hz), 3.0-3.8(6H, m), 3.42(1H, dd, J₁=6.5 Hz, J₂=3.2 Hz), 3.6(1H, m),4.28(1H, m), 4.48(1H, dd, J₁=10.4 Hz, J₂=3.2 Hz), 5.70(1H, d, J=5.6 Hz),5.83(1H, d, J=5.6 Hz), 7.18(1H, s), 7.74(1H, s).

Example 144(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 29.7 mg from 46 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and69.6 mg of 7-cyano-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.41(3H, d, J=6.3 Hz), 3.39(3H, m), 4.33(1H, m), 4.47(1H,m), 5.23(1H, d, J=13.3 Hz), 5.39(1H, d, J=13.3 Hz), 7.18(1H, s),7.54(2H, d, J=8.4 Hz), 7.69(1H, s), 8.22(2H, d, J=8.4 Hz).

b)(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 35.4 mg from 124 mg of 4-nitrobenzyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.32(3H, d, J=6.4 Hz), 3.23(1H, dd, J₁=17.3Hz, J₂=9.9 Hz), 3.46(1H, dd, J₁=17.3 Hz, J₂=8.3 Hz), 3.60(1H, dd, J₁=6.0Hz, J₂=2.9 Hz), 4.28(1H, m), 4.39(1H, m), 7.27(1H, s), 7.98(1H, s).

Example 145 Pivaloyloxymethyl(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 23.2 mg from 31.1 mg of(5R,6S)-2-(7-cyanoimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylicacid.

NMR (CDCl₃) δ: 1.20(9H, s), 1.38(3H, d, J=6.3 Hz), 3.38(3H, m), 4.30(1H,m), 4.4(1H, m), 5.76(1H, d, J=5.6 Hz), 5.88(1H, d, J=5.6 Hz), 7.20(1H,s), 7.76(1H, s).

Example 146(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylicAcid

a) 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 5-a), 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylatewas obtained in a yield of 217.6 mg from 264.3 mg of 4-nitrobenzyl(3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and379.2 mg of7-(N-methylcarbamoyl)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.

NMR (CDCl₃) δ: 1.41(3H, d, J=6.3 Hz), 3.01(3H, d, J=5.0 Hz),3.32-3.40(3H, m), 4.30-4.40(3H, m), 5.32(1H, d, J=13.8 Hz), 5.54(1H, d,J=13.8 Hz), 6.86(1H, br.s, s), 7.69(2H, d, J=8.4 Hz), 7.92(1H, s),8.25(2H, d, J=8.4 Hz), 8.49(1H, s). MS (TSP): 512 (M⁺+H).

b)(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylicAcid

In the same manner as in Example 5-b), the title compound was obtainedin a yield of 61 mg from 116.2 mg of 4-nitrobenzyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.

NMR (D₂O) δ (HOD=4.80 ppm): 1.30(3H, d, J=6.5 Hz), 2.90(3H, s),3.15-3.21(2H, m), 3.42-3.48(1H, m), 4.18-4.30(2H, m), 7.65(1H, s),7.93(1H, s).

Example 147 Pivaloyloxymethyl(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate

In the same manner as in Example 19, the title compound was obtained ina yield of 23.0 mg from 41.8 mg of(5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methylcarbamoyl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylateand 0.023 ml of pivaloyloxymethyl iodide.

NMR (CDCl₃) δ: 1.22(9H, s), 1.37(3H, d, J=6.3 Hz), 1.18(1H, br.s, s),3.01(3H, d, J=5.1 Hz), 3.29-3.37(3H, m), 4.26-4.38(2H, m), 5.90(1H, d,J=5.6 Hz), 6.01(1H, d, J=5.6 Hz), 6.89(1H, br.s, s), 7.95(1H, s),8.58(1H, s). MS (FAB⁺): 491 (M⁺+H).

Example 148 Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer)

a) 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer)

In the same manner as in Example 5-a), 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]-thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer) was obtained in a yield of 252 mg from 452 mg of4-nitrobenzyl(1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylateand 704 mg of7-methoxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazoledescribed in Preparation 15 (geometrical isomer derived from a rawmaterial which is a low polar oxime isomer).

NMR (CDCl₃) δ: 1.32(3H, d, J=7.2 Hz), 1.39(3H, d, J=6.1 Hz), 3.38(1H,dd, J₁=6.4 Hz, J₂=2.8 Hz), 3.52(1H, m), 3.96(3H, s), 4.33(1H, m),4.40(1H, dd, J₁=9.6 Hz, J₂=2.8 Hz), 5.28(1H, d, J=13.7 Hz), 5.53(1H, d,J=13.7 Hz), 7.67(2H, d, J=8.2 Hz), 8.03(1H, s), 8.22(1H, s), 8.23(2H, d,J=8.2 Hz), 8.44(1H, s).

b) Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer)

In the same manner as in Example 134-d), the title compound was obtainedin a yield of 90.8 mg from 252 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]-thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer).

NMR (D₂O) δ (HOD=4.80 ppm): 1.22(3H, d, J=6.9 Hz), 1.33(3H, d, J=6.3Hz), 3.53(2H, m), 3.93(3H, s), 4.30(2H, m), 7.85(1H, s), 8.05(2H, 2s).

Example 149 Pivaloyloxynethyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer)

In the same manner as in Example 135, the title compound was obtained ina yield of 96.2 mg from 105 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate(geometrical isomer derived from a raw material which is a low polaroxime isomer).

NMR (CDCl₃) δ: 1.20(9H, s), 1.30(3H, d, J=7.2 Hz), 1.37(3H, d, J=6.2Hz), 3.34(1H, dd, J₁=6.3 Hz, J₂=2.7 Hz), 3.49(1H, m), 3.97(3H, s),4.30(1H, m), 4.37(1H, dd, J₁=9.8 Hz, J₂=2.7 Hz), 5.88(1H, d, J=5.6 Hz),6.00(1H, d, J=5.6 Hz), 8.07(1H, s), 8.23(1H, s), 8.44(1H, s).

The structures of the compounds in Examples above are illustrated below.

In this connection, * represents the linkage with the position 2 on thecarbapenam ring, and POM represents a pivaloyloxymethyl group.

R¹ R² R³ R⁴ R⁵ R⁶ R 1.2 CH₃ * H H H — H 3 CH₃ * H H H — POM 4 CH₃ * H HH CH₃ — 5 CH₃ H * H H — H 6 CH₃ H * H H — POM 7 CH₃ H * H H CH₃ — 8 H *H H H — H 9 CH₃ * CH₃ H H — H 10 CH₃ * CH₃ H H — POM 11 CH₃ * CH₃ H HCH₃ — 12 H H * H H — H 13 H H * H H — POM 14 H H * H H CH₃ — 15 H * H HH CH₃ — 16 CH₃ * H H H CH₂CONH₂ — 17 CH₃ * H CH₃ H — H 18 CH₃ * H CH₃ HCH₃ — 19 CH₃ * H CH₃ H — POM 20 CH₃ * H H Cl — H 21 CH₃ CH₃ * H H — H 22H CH₃ * H H — H 23 CH₃ * H H Cl CH₃ — 24 H * H H H — POM 25 H * H CH₃ H— H 26 H * H CH₃ H — POM 27 CH₃ * H H CH₃ — Na 28 CH₃ * H H CH₃ — POM 29CH₃ * H H CH₃ CH₃ — 30 H * H CH₃ H CH₃ — 31 CH₃ * H CH₂NHCHO H — H 32CH₃ * H CH₂NHCHO H — POM 33 CH₃ * H CH₂NHCHO H CH₃ — 34 CH₃ * H CH₂OH H— H 35 CH₃ * H CH₂OH H — POM 36 CH₃ * CH₂OH H H — H 37 CH₃ H * H CH₃ — H38 H * H H CH₃ — Na 39 H * H H CH₃ — POM 40 CH₃ H * H CH₃ — POM 41 CH₃ *H CH₂OH H CH₃ — 42 H * H H CH₃ CH₃ — 43 H H * H CH₃ — H 44 H H * H CH₃ —POM 45 H H * H CH₃ CH₃ — 46 H * CH₃ H H — H 47 H * CH₃ H H — POM 48 CH₃H H * H — K 49 CH₃ * H H CH₂NHCHO CH — 50 CH₃ H H * H — POM 51 CH₃ * CH₃H H CH₃ 52 CH₃ * H H H — CH₂OC(O)CH₃ 53 CH₃ * H H H — CH(CH₃)OC(O)CH₃ 54CH₃ * H H H —

55 CH₃ * H H H — CH(CH₃)OC(O)OCH₂CH₃ 56 CH₃ * H H H —CH(CH₃)OC(O)OCH(CH₃)₂ 57 CH₃ * H H H —

58 CH₃ * H H H —

59 CH₃ * H H H —

60 CH₃ * H H H —

61 CH₃ * H H H —

62 CH₃ * H H H —

63 CH₃ * H H H —

64 CH₃ * H H H —

65 CH₃ * H H H —

66 CH₃ * H H H —

67 CH₃ * H H H —

68 CH₃ * H H H —

69 CH₃ * H H H —

70 CH₃ * H CONH₂ H — H 71 CH₃ * H CONH₂ H — POM 72 H H H * H — K 73 H HH * H — POM 74 CH₃ * H CHO H — H 75 CH₃ * H CHO H — POM 76 CH₃ * H HCH₂OH — H 77 CH₃ * H H CH₂OH CH₃ — 78 CH₃ H H H * — K 79 CH₃ H H H * CH₃— 80 H * H H Cl — Na 81 H * H CONH₂ H — H 82 H * H CONH₂ *H — POM 83CH₃ * H CHO H CH₃ — 84 CH₃ H H H * * POM 85 CH₃ * H H CH₂OH — POM 86 H *H H Cl CH₃ — 87 H * H H Cl — POM 88 H * H H H CH₂CONH₂ — 89 CH₃ * H CH₃CH₃ — Na 90 CH₃ * H H CH₂NHCHO — Na 91 H H * H H — CH₂OC(O)CH₃ 92 H H *H H — CH(CH₃)OC(O)CH₃ 93 H H * H H —

94 H H * H H — CH(CH₃)OC(C)OCH₂CH₃ 95 H H * H H — CH(CH₃)OC(O)OCH(CH₃)₂96 H H * H H —

97 H H * H H —

98 H H * H H —

99 H H * H H —

100 CH₃ * H H CH₂NHCHO — POM 101 H H * H CH₂NHCHO — Na 102 H H * HCH₂NHCHO — POM 103 H H * H CONH₂ — H 104 H H * H CONH₂ — POM 105 CH₃ * HCH₃ CH₃ CH₃ — 106 H H * H CH₂OH — Na 107 CH₃ * H H CHO — N 108 CH₃ * H HCHO — POM 109 CH₃ * H H CONH₂ — H 110 CH₃ * H H CONH₂ — POM 111 CH₃ * HH CH₂OCH₃ — Na 112 CH₃ * H H CH₂OCH₃ — POM 113 H H * H CH₂OCH₃ — Na 114H H * H CH₂OCH₃ — POM 115 H H * H CH₂OH — POM 116 CH₃ * H H CN — H 117CH₃ * H H CN — POM 118 CH₃ * H H CH₂CH₃ — H 119 CH₃ * H H CH₂CH₃ — POM120 H H * CONH₂ H — H 121 H * H H CH₂CH₃ — H 122 H * H H CH₂CH₃ — POM123 H H * H CH₂CH₃ — H 124 H H * H CH₂CH₃ — POM 125 H * H H CN — H 126H * H H CN — POM 127 CH₃ * H H CH₂CH₃ CH₃ 128 H * H CH₃ CH₃ — H 129 H *H CH₃ CH₃ — POM 130 H H * H CHO — H 131 H H * H CHO — POM 132 H H * HCH₂CH₃ CH₃ — 133 H * H CH₃ CH₃ CH₃ — 134 CH₃ * H H C(O)CH₃ — Na 135CH₃ * H H C(O)CH₃ — POM 136 H H * H C(O)CH₃ — H 137 CH₃ * H H CH═NOCH₃ —H 138 CH₃ * H H C(O)NHCH₃ — H 139 CH₃ * H H C(O)NHCH₃ — POM 140 CH₃ * HH C(O)N(CH₃)₂ — Na 141 CH₃ * H H C(O)N(CH₃)₂ — POM 142 CH₃ H * HC(O)N(CH₃)₂ — Na 143 CH₃ H * H C(O)N(CH₃)₂ — POM 144 H H * H CN — H 145H H * H CN — POM 146 H * H H C(O)NHCH₃ — H 147 H * H H C(O)NHCH₃ — POM148 CH₃ * H H CH═NOCH₃ — Na 149 CH₃ * H H CH═NOCH — POM

Preparation Example 1

Injection

The compound of Example 1 is aseptically dispensed in a vial in anamount of 1000 mg (titer).

Preparation Example 2

Capsule

Compound of Example 3 250 parts (titer) Lactose 60 parts (titer)Magnesium stearate 5 parts (titer)

The components were mixed homogeneously and filled into a capsule in anamount of 250 mg (titer)/capsule.

Preparation Example 3

Soft Capsule for Rectal Dosage

Olive oil 160 parts (titer) Polyoxyethylene lauryl ether 10 parts(titer) Sodium hexamethanoate 5 parts (titer)

The compound of Example 3 in an amount of 25 parts (titer) was added toand mixed with the base consisting of the components, and filled into asoft capsule for rectal dosage in an amount of 250 mg(titer)/capsule.

Test 1

Anti-microbial Activities

The minimum inhibiting concentrations (MIC, μMg/ml) of the compoundsaccording to the present invention to various pathogenic bacteria wasmeasured in accordance with the method described in CHEMOTHERAPY, vol.16, No. 1, 99, 1968. The culture medium for measurement was SensitivityDisk agar-N+5% Horse blood, and the amount of inoculants was 10⁶ CFU/ml.

The results are shown in the following table.

Com- Com- Example Example Example pound pound Organism 1 4 8 A B S.aureus <0.025 <0.025 <0.025 <0.025 <0.025 209P JC-1 S. aureus 3.13 3.136.25 25 6.25 M126* S. epidermidis <0.025 <0.025 0.05 <0.025 0.05ATCC14990 E. hirae 0.39 0.78 0.78 0.78 1.56 ATCC8043 E. faecalis 0.200.10 0.39 0.78 3.13 W-73 S. pneumoniae 0.10 0.05 0.20 0.20 0.39 PRC9**B. catarrhalis <0.025 <0.025 <0.025 <0.025 <0.025 W-0506 H. influenzae<0.025 0.05 0.05 0.78 0.10 PRC2 H. influenzae 0.39 0.39 0.78 12.5 0.78PRC44 E. coli 0.10 <0.025 0.10 0.10 0.05 NIHJ JC-2 K. pneumoniae 0.100.05 0.05 0.20 0.10 PCI602 P. vulgaris 0.05 0.10 0.10 0.10 0.10 GN7919C. freundii 1.56 0.10 0.20 0.20 0.10 GN346

In the table,

*: methicillin-hyper resistant strain (MRSA);

**: penicillin-hyper resistant strain (PRSP);

Compound A: imipenem;

Compound B:(1R,5S,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[(3S,5S)-5-(6-methylimidazo[5,1-b]thiazolium-2-yl)methylpyrrolidin-3-yl]thiocarbapen-2-em-3-carboxylicacid iodide.

As is apparent from the above described test results, the compoundsaccording to the present invention have strong anti-microbial activitiesagainst MRSA, PRSP, enterococci, influenza as well as various pathogenicbacteria including β-lactamase producing bacteria.

Test 2

Stability Against DHP-I

The stabilities of the compounds according to the present inventionagainst porcine and mouse renal dehydropeptidases were measured by thefollowing method.

(1) Preparation of DHP-1 from kidney acetone powders of various animals

Kidney acetone powder, Porcine Type II(Sigma; Lot. 33H7225; 1.5 g) wassuspended in a 50 mM Tris.HCl buffer (pH 7.0) containing 20% butanol,and the mixture was stirred at 5° C. for 48 hours. Dialysis (Cellulosetube 30/32; Viskase Sales Corp) was conducted with a 50 mM Tris.HClbuffer (pH 7.0) in order to remove butanol to a level of no smell ofbutanol. The dialysate was centrifuged at 10000×g (KUBOTA 6800) for 20minutes to give a supernatant as a partly purified DHP-I, which wasdivided into portions and stored at −80° C. Also, a partly purifiedDHP-I was prepared from 1.5 g of Mouse (Lot. 23F8105), and stored in thesame manner as above.

(2) Measurement of stabilities to various DHP-I's

The compounds according to the present invention as a basicpharmaceutical was diluted with sterile purified water to prepare asolution having a titer of 2000 μg/ml. The solution of the compoundaccording to the present invention having a titer of 2000 μg/ml wasadded to the partly purified DHP-I's of the above described animals soas to have a final concentration of 100 μg (titer)/ml. As a blank, 50 mMTris.HCl buffer (pH 7.0) was used in place of the partly purifiedDHP-I's of the animals. After reaction at 37° C. for 3 hours, a portionof the reaction mixture was taken out, diluted with the same amount ofmethanol to stop the reaction by cooling in ice. The reaction mixturewas filtered through SUNPLEP LCR13-LH, MILLIPORE), and subjected to HPLC(column: CAPCELL PACK C18 SG120, SHISEIDO; UV detector; mobile phase:acetonitrile—10 mM aqueous acetic acid solution) to measure the residualamount (%) of the partly purified DHP-I according to the followingequation.${{Residual}\quad {amount}\quad (\%)} = {\frac{{Sample}\quad {peak}\quad {area}}{{Blank}\quad {peak}\quad {area}} \times 100}$

The residual amounts (%) of the compounds according to the presentinvention after 3 hours are shown below.

Com- Com- DHP-I Example 1 Example 4 Example 8 pound A pound C Porcine 87100 60 0.6 72 Mouse <2.9 94 <0.2 24 18

In the table, Compound A: imipenem;

Compound B: meropenem.

It is understood from the above table that the compounds according tothe present invention have high stabilities to the porcine renal DHP-I,and the carbapenei derivatives represented by the general formula (II)have high stabilities to both of the porcine and mouse renal DHP-I.

Test 3

Oral Absorption Ability Test

The compound of Example 3 was orally administered to mice (ICR, male,n=3) in an amount of 0.5 mg (based on the weight of the compound ofExample 1 from which the compound of Example 3 is derived)/0.2 ml/mouseas a 0.5% methylcellulose suspension, and then cilastatin wasimmediately administered subcutaneously in the same amount (because ofthe instability of the compound of Example 1 to mouse DHP-I, cilastatinas an inhibitor of DHP-I was used in combination). As a result, thecompound of Example 1 was excreted in urine in an amount of 36% of thedose by 8 hours after administration.

Test 4

Acute Toxicity Test

The compound of Example 1 was administered intravenously to mice (ICR,male, n =3) in an amount of 2000 mg/kg. As a result, all of the animalswere survived.

What is claimed is:
 1. A compound represented by the formula (I), or apharmaceutically acceptable salt thereof:

wherein R¹ represents a hydrogen or methyl, R², R³, R⁴, and R⁵, eitherone of which represents the bond to the 2-position on the carbapenemring, and the other three of which-may be the same or different,respectively represent hydrogen, halogen, nitro, cyano, lower alkyl, inwhich one or more hydrogen atoms on the alkyl group may be substitutedby groups selected from the group consisting of halogen, nitro, cyano,lower cycloalkyl, lower alkylthlio, lower alkoxy, hydroxy, amino,N-lower alkylamino, formyl, lower alkylcarbonyl, aryl carbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-loweralkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,lower cycloalkyl, in ewhich one or more hydrogen atoms on the cycloalkylgroup may be substituted by groups selected from the group consisting oflower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy,hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylanmino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,lower alkylthio, C₂₋₄ alkenyl, in which one or more hydrogen atoms onthe alkenyl group may be substituted by groups selected from the groupconsisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl,lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino,formyl, lower alkylcarbonlyl, aryl carbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl, formyl, lower alkylcarbonyl, loweralkoxycarbonyl, lower alkylsulfonyl, lower arylsulfonyl, aminosulfonyl,aryl carbonyl, aryl, in which one or more hydrogen atoms on the arylgroup may be substituted by groups selected from the group consisting oflower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio,lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, loweralkylcarbonyl, aryl carbonyl, carboxyl, lower alkoxycarbonyl,formylamino, lower alkylcarbonylamino, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-loweralkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-loweralkylamino)sulfonylamino, aminosulfonylamino, and (N,N-di-loweralkylamino)sulfonylamino, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylaminocarbonyl, lower alkoxyiminomethyl, orhydroxyiminomethyl, R⁶ is not present or represents lower alkyl, inwhich one or more hydrogen atoms on the alkyl group may be substitutedby groups selected from the group consisting of halogen, nitro, cyano,lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-loweralkylamino, formyl, lower alkylcarbonyl, aryl carbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl, lower cycloalkyl, in which one ormore hydrogen atoms on the cycloalkyl group may be substituted by groupsselected from the group consisting of lower alkyl, halogen, nitro,cyano, lower alkylthio, lower alkoxy, hydroxy, amino, N-loweralkylamino, formyl, lower alkylcarbonyl, aryl carbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkcylaminocarbonyl, aminosulfonyl,(N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl,(N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino)sulfonylamino, and aryl, or C₂₋₄ alkenyl, in which one ormore hydrogen atoms on the alkenyl group may be substituted by groupsselected from the group consisting of lower alkyl, halogen, nitro,cyano, lower cycloalkyl, lower alkylthio, lower alkoyy, hydroxy, amino,N-lower alkylamino, formyl, lower alkylcarbonyl, aryl carbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonyl amino,carbamoyl, N-lower alkylcarbaioyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-loweralkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,and R is not present, or represents hydrogen or a group which may bemetabolically hydrolyzed in the body, provided that when R⁶ is notpresent, R represents hydrogen or group may be metabolically hydrolyzedin the body, and when R⁶ is present, R is not present and the compoundforms an inner salt.
 2. A compound according to claim 1, wherein R⁶ isnot present, and R represents hydrogen or a group may be metabolicallyhydrolyzed in the body.
 3. A compound according to claim 2, wherein R¹represents hydrogen or methyl, R², R³, R⁴, and R⁵, except the one whichrepresents the bond to the 2-position on the carbapenem ring, which maybe the same or different, and respectively represent hydrogen, halogen,cyano, lower alkyl, in which one or more hydrogen atoms on the alkylgroup may be substituted by groups selected from the group consisting ofhalogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy,hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower allkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower,alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,formyl, lower alkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl,lower alkoxyiminomethyl, or hydroxyiminomethyl.
 4. A compound accordingto claim 3, wherein the lower alkyl is unsubstituted or substituted bylower alkoxy, hydroxy, or formylamino.
 5. A compound according to anyone of claims 2-4, wherein R represents lower alkylcarbonyloxy loweralkyl, lower cycloalkylcarbonyloxy lower alkyl, loweralkyloxycarbonyloxy lower alkyl, lower cycloalkyloxycarbonyloxy loweralkyl, lower cycloalkylmethoxycarbonyloxy lower alkyl,aryloxycarbonyloxy lower alkyl, 2-oxo-5-loweralkyl-1,3-dioxolene-4-ylmethyl, 3-phthalidyl of which the aromatic ringmay be substituted by lower alkyl, halogen, nitro, cyano, lowercycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-loweralkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, loweralkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl,(N-lower alkylamino) sulfonyl, (N,N-di-lower alkylamino) sulfonyl,(N-lower alkylamino) sulfonylamino, aminosulfonylamino, (N,N-di-loweralkylamino) sulfonylamino, or aryl, or 2-(3-phthalidylidene)ethyl ofwhich the aromatic ring may be substituted by lower alkyl, halogen,nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy,amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl,carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl,aminosulfonyl, (N-lower alkylamino) sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino) sulfonylamino, aminosulfonylamino,(N,N-di-lower alkylamino) sulfonylamino, or aryl.
 6. A compoundaccording to claim 2, wherein R¹ represents methyl, R² represents thebond to the 2-position on the carbapenem ring, and R³, R⁴, and R⁵, whichmay be the same or different, respectively represent hydrogen, halogen,cyano, lower alkyl, in which one or more hydrogen atoms on the alkyl maybe substituted by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 7. A compound according toclaim 2, wherein R¹ represents hydrogen, R² represents the bond to the2-position on the carbapenem ring, and R³, R⁴, and R⁵, which may be thesame or different, respectively represent hydrogen, halogen, cyano,lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 8. A compound according toclaim 2, wherein R¹ represents methyl, R³ represents the bond to the2-position on the carbapenem ring, and R², R⁴, and R⁵, which may be thesame or different, respectively represent hydrogen, halogen, cyano,lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstututed by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 9. A compound according toclaim 2, wherein R¹ represents hydrogen, R³ represents the bond to the2-position on the carbapenem ring, and R², R⁴, and R⁵, which may be thesame or different, respectively represent hydrogen, halogen, cyano,lower alkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 10. A compound according toclaim 2, wherein R¹ represents hydrogen or methyl, R⁴ represents thebond to the 2-position on the carbapenem ring, and R², R³, and R⁵, whichmay be the same or different, respectively represent hydrogen, halogen,cyano, lower alkyl, in which one or more hydrogen atoms may besubstituted by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 11. A compound according toclaim 2, wherein R¹ represents hydrogen or methyl, R⁵ represents thebond to the 2-position on the carbapenem ring, and R², R³, and R⁴, whichmay be the same or different, respectively represent hydrogen, halogen,cyano, lower alkyl, in which one or more hydrogen atoms may besubstituted by lower alkoxy, hydroxy, or formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl.
 12. A compound according toclaim 1, wherein R⁶ is present, R is not present, and the compound formsan inner salt.
 13. A compound according to claim 12, wherein R¹represents hydrogen or methyl, and R², R³, R⁴, R⁵, and R⁶, except theone representing the bond to the 2-position on the carbapenem ring,which may be the same or different, respectively represent hydrogen,halogen, cyano, lower alkyl, in which one or more hydrogen atoms on thealkyl may be substituted by a group selected from the group consistingof halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, loweralkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl,aryl carbonyl, carboxyl, lower alkoxycarbonyl, formylamino, loweralkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl,(N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino,aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl,formyl, lower alkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl,lower alkoxyiminomethyl, or hydroxyiminomethyl.
 14. A compound accordingto claim 13, wherein R², R³, R⁴, and R⁵, except the one representing thebond to the 2-position on the carbapenem ring, represent hydrogen,halogen, cyano, lower alkyl, in which one or more hydrogen atoms on thealkyl may be substituted by a group selected from the group consistingof lower alkoxy, hydroxy, and formylamino, formyl, lower alkylcarbonyl,lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylaminocarbonyl, lower alkoxyiminomethyl, orhydroxyiminomethyl, and R⁶ represents lower alkyl which may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, formylamino, and carbamoyl.
 15. A compound according toclaim 12, wherein R¹ represents methyl, R² represents the bond to the2-position on the carbapenem ring, R³, R⁴, and R⁵, which may be the sameor different, respectively represent hydrogen, halogen, cyano, loweralkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, and formylamino, formyl, lower alkylcarbonyl, loweralkoxycarbonyl, aminosulfonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylaminocarbonyl, lower alkoxyiminomethyl, orhydroxyiminomethyl, and R⁶ represents lower alkyl which may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, formylamino, and carbamoyl.
 16. A compound according toclaim 12, wherein R¹ represents hydrogen, R² represents the bond to the2-position on the carbapenem ring, R³, R⁴, and R⁵, which may be the sameor different, respectively represent hydrogen, halogen, cyano, loweralkyl, in which one or more hydrogen atoms on the alkyl may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, and formylamino, formyl, lower alkylcarbonyl, loweralkoxycarbonyl, aminosulfonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylaminocarbonyl, lower alkoxyiminomethyl, orhydroxyiminomethyl, and R⁶ represents lower alkyl which may besubstituted by a group selected from the group consisting of loweralkoxy, hydroxy, formylamino, and carbamoyl.
 17. A compound according toclaim 12, wherein R¹ represents methyl, R³ represents the bond to the2-position on the carbapenem ring, R², R⁴ and R⁵, which may be the sameor different, respectively represent hydrogen, halogen, cyano, loweralkyl, in which one or more hydrogen atoms may be substituted by a groupselected from the group consisting of lower alkoxy, hydroxy, andformylamino, formyl, lower alkylcarbonyl, lower alkoxycarbonyl,aminosulfonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylaminocarbonyl, lower alkoxyiminomethyl, or hydroxyiminomethyl, andR⁶ represents lower alkyl which may be substituted by a group selectedfrom the group consisting of lower alkoxy, hydroxy, formylamino, andcarbamoyl.
 18. A compound according to claim 12, wherein R¹ representshydrogen, R³ represents the bond to the 2-position on the carbapenemring, R², R⁴, and R⁵, which may be the same or different, respectivelyrepresent hydrogen, halogen, cyano, lower alkyl, in which one or morehydrogen atoms on the alkyl may be substituted by a group selected fromthe group consisting of lower alkoxy, hydroxy, and formylamino, formyl,lower alkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl, and R⁶ represents lower alkylwhich may be substituted by a group selected from the group consistingof lower alkoxy, hydroxy, formylamino, and carbamoyl.
 19. A compoundaccording to claim 12, wherein R¹ represents hydrogen or methyl, R⁴represents the bond to the 2-position on the carbapenem ring, R², R³,and R⁵, which may be the same or different, respectively representhydrogen, halogen, cyano, lower alkyl, in which one or more hydrogenatoms on the alkyl may be substituted by a group selected from the groupconsisting of lower alkoxy, hydroxy, and formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl, and R⁶ represents lower alkylwhich may be substituted by a group selected from the group consistingof lower alkoxy, hydroxy, formylamino, and carbamoyl.
 20. A compoundaccording to claim 12, wherein R¹ represents hydrogen or methyl, R⁵represents the bond to the 2-position on the carbapenem ring, R², R³,and R⁴, which may be the same or different, respectively representhydrogen, halogen, cyano, lower alkyl, in which one or more hydrogenatoms on the alkyl may be substituted by a group selected from the groupconsisting of lower alkoxy, hydroxy, and formylamino, formyl, loweralkylcarbonyl, lower alkoxycarbonyl, aminosulfonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, loweralkoxyiminomethyl, or hydroxyiminomethyl, and R⁶ represents lower alkylwhich may be substituted by a group selected from the group consistingof lower alkoxy, hydroxy, formylamino, and carbamoyl.
 21. A compoundaccording to claim 1, wherein R² or R³ represents the bond to the2-position on the carbapenem ring.
 22. A compound according to claim 1,wherein R⁶ represents alkyl having one or two carbon atoms which may besubstituted by carbamoyl, fluorine, or hydroxy.
 23. A compound accordingto claim 1, wherein R² represents the bond to the 2-position on thecarbapenem ring, all of R³, R⁴, and R⁵ represent hydrogen, or both R³and R⁴ represent hydrogen, and R⁵ represents a group selected from thegroup consisting of lower alkyl which may be substituted by formylaminoor lower alkoxy, chlorine, formyl, lower alkylcarbonyl, cyano,carbamoyl, N-lower alkylcarbamoyl, and N,N-di-lower alkylaminocarbonyl.24. A compound according to claim 1, wherein R² represents the bond tothe 2-position on the carbapenem ring, R³ represents methyl.
 25. Acompound according to claim 1, wherein R³ represents the bond to the2-position on the carbapenem ring, both R² and R⁴ represent hydrogen,and R⁵ represents hydrogen or cyano.
 26. A pharmaceutical compositioncomprising the compound according to claim 1, and a pharmacologicallyacceptable carrier.
 27. A method for treating bacterial infectiousdiseases, comprising administering the compound according to any one ofclaims 1-4 or 6-25 to an animal including humans.
 28. A pharmaceuticalcomposition comprising the compound according to claim 5, and apharmacologically acceptable carrier.
 29. A method for treatingbacterial infectious diseases, comprising administering the compoundaccording to claim 5 to an animal including humans.